Publications by authors named "Xiao-Jun Du"

155 Publications

Loss of the long non-coding RNA OIP5-AS1 exacerbates heart failure in a sex-specific manner.

iScience 2021 Jun 13;24(6):102537. Epub 2021 May 13.

Baker Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.

Long non-coding RNAs (lncRNAs) have been demonstrated to influence numerous biological processes, being strongly implicated in the maintenance and physiological function of various tissues including the heart. The lncRNA OIP5-AS1 (/C) has been studied in several settings; however its role in cardiac pathologies remains mostly uncharacterized. Using a series of and methods, we demonstrate that OIP5-AS1 is regulated during cardiac development in rodent and human models and in disease settings in mice. Using CRISPR, we engineered a global OIP5-AS1 knockout (KO) mouse and demonstrated that female KO mice develop exacerbated heart failure following cardiac pressure overload (transverse aortic constriction [TAC]) but male mice do not. RNA-sequencing of wild-type and KO hearts suggest that OIP5-AS1 regulates pathways that impact mitochondrial function. Thus, these findings highlight OIP5-AS1 as a gene of interest in sex-specific differences in mitochondrial function and development of heart failure.
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http://dx.doi.org/10.1016/j.isci.2021.102537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184514PMC
June 2021

AMPK upregulates K2.3 channels and ameliorates endothelial dysfunction in diet-induced obese mice.

Biochem Pharmacol 2021 01 11;183:114337. Epub 2020 Nov 11.

Department of Physiology and Pathophysiology, Cardiovascular Research Centre, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an 710061, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an 710061, Shaanxi, China. Electronic address:

The opening of endothelial small-conductance calcium-activated potassium channels (K2.3) is essential for endothelium-dependent hyperpolarization (EDH), which predominantly occurs in small resistance arteries. Adenosine monophosphate-activated protein kinase (AMPK), an important metabolic regulator, has been implicated in regulating endothelial nitric oxide synthase activity. However, it was unclear whether AMPK regulated endothelial K2.3-mediated EDH-type vasodilation. Using bioinformatics analysis and myograph system, we investigated the regulation by AMPK of K2.3 in human umbilical vein endothelial cells (HUVECs) or mouse second-order mesenteric resistance arteries. In HUVECs, AMPK activation either by activators (AICAR, A769662 and MK-8722) or expression of the constitutively active form of AMPK significantly upregulated K2.3 expression. Such effects were abolished by AMPK inhibitor (compound C) or AMPK α1-/α2-siRNA, extracellular-signal-regulated-kinase 5 (ERK5) inhibitor (ERK5-IN-1), and specific siRNA to myocyte-enhancer factor 2 (MEF2) or krüppel-like factor 2/4 (KLF2/4). K2.3 expression was significantly reduced in mesenteric resistance arteries in AMPKα2 knockout mice when compared with littermate control mice. Furthermore, in high-fat diet fed mice, 2-week treatment with AICAR restored endothelial K2.3 expression in mesenteric resistance arteries with improved endothelial dysfunction. Our results demonstrate that activation of AMPK upregulates K2.3 channel expression through the ERK5-MEF2-KLF2/4 signaling pathway in vascular endothelium, which contributes to benefits through K2.3-mediated EDH-type vasodilation in mesenteric resistance arteries.
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http://dx.doi.org/10.1016/j.bcp.2020.114337DOI Listing
January 2021

Manipulation of the gut microbiota by the use of prebiotic fibre does not override a genetic predisposition to heart failure.

Sci Rep 2020 10 21;10(1):17919. Epub 2020 Oct 21.

Heart Failure Research Group, Baker Heart and Diabetes Institute, St Kilda Rd Central, PO Box 6492, Melbourne, VIC, 8008, Australia.

Increasing evidence supports a role for the gut microbiota in the development of cardiovascular diseases such as hypertension and its progression to heart failure (HF). Dietary fibre has emerged as a modulator of the gut microbiota, resulting in the release of gut metabolites called short-chain fatty acids (SCFAs), such as acetate. We have shown previously that fibre or acetate can protect against hypertension and heart disease in certain models. HF is also commonly caused by genetic disorders. In this study we investigated whether the intake of fibre or direct supplementation with acetate could attenuate the development of HF in a genetic model of dilated cardiomyopathy (DCM) due to overexpression of the cardiac specific mammalian sterile 20-like kinase (Mst1). Seven-week-old male mice DCM mice and littermate controls (wild-type, C57BL/6) were fed a control diet (with or without supplementation with 200 mM magnesium acetate in drinking water), or a high fibre diet for 7 weeks. We obtained hemodynamic, morphological, flow cytometric and gene expression data. The gut microbiome was characterised by 16S rRNA amplicon sequencing. Fibre intake was associated with a significant shift in the gut microbiome irrespective of mouse genotype. However, neither fibre or supplementation with acetate were able to attenuate cardiac remodelling or cardiomyocyte apoptosis in Mst1 mice. Furthermore, fibre and acetate did not improve echocardiographic or hemodynamic parameters in DCM mice. These data suggest that although fibre modulates the gut microbiome, neither fibre nor acetate can override a strong genetic contribution to the development of heart failure in the Mst1 model.
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http://dx.doi.org/10.1038/s41598-020-73614-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578080PMC
October 2020

Endothelial-specific overexpression of cationic amino acid transporter-1 prevents loss of kidney function in heart failure.

Clin Sci (Lond) 2020 10;134(20):2755-2769

Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, Australia.

Heart failure (HF) is associated with impaired L-arginine transport. In the present study, we tested the hypothesis that augmented L-arginine transport prevents the loss of kidney function in HF. Renal function was assessed in wildtype mice (WT), transgenic mice with HF (dilated cardiomyopathy, DCM) and double transgenic mice (double transgenic mice with DCM and CAT-1 overexpression, HFCAT-1) with HF and endothelial-specific overexpression of the predominant L-arginine transporter, cationic amino acid transporter-1 (CAT-1) (n=4-8/group). Cardiac function was assessed via echocardiography and left ventricular catheterisation. Renal function was assessed via quantification of albuminuria and creatinine clearance. Plasma nitrate and nitrite levels together with renal fibrosis and inflammatory markers were also quantified at study end. Albumin/creatinine ratio was two-fold greater in DCM mice than in WT mice (P=0.002), and tubulointerstitial and glomerular fibrosis were approximately eight- and three-fold greater, respectively, in DCM mice than in WT mice (P≤0.02). Critically, urinary albumin/creatinine ratio and tubulointerstitial and glomerular fibrosis were less in HFCAT-1 mice than in DCM mice (P<0.05). Renal CAT-1 expression and plasma nitrate and nitrite levels were less in DCM mice compared with WT (P≤0.03) but was greater in HFCAT-1 mice than in DCM mice (P≤0.009). Renal expression of IL-10 was less in DCM mice compared with WT (P<0.001) but was greater in HFCAT-1 mice compared with DCM mice (P=0.02). Our data provide direct evidence that augmented L-arginine transport prevents renal fibrosis, inflammation and loss of kidney function in HF.
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http://dx.doi.org/10.1042/CS20200087DOI Listing
October 2020

Correction to: Cardiac rupture complicating acute myocardial infarction: the clinical features from an observational study and animal experiment.

BMC Cardiovasc Disord 2020 Oct 8;20(1):441. Epub 2020 Oct 8.

Department of Cardiovascular Medicine, First Affiliated Hospital, School of Medicine of Xi'an Jiaotong University, No.277 Yanta West Road, Xi'an, Shaanxi, 710061, P. R. China.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s12872-020-01713-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542902PMC
October 2020

Cardiac rupture complicating acute myocardial infarction: the clinical features from an observational study and animal experiment.

BMC Cardiovasc Disord 2020 09 10;20(1):409. Epub 2020 Sep 10.

Department of Cardiovascular Medicine, First Affiliated Hospital, School of Medicine of Xi'an Jiaotong University, No.277 Yanta West Road, Xi'an, Shaanxi, 710061, P.R. China.

Background: Cardiac rupture (CR) is a fatal complication of ST-elevation myocardial infarction (STEMI) with its incidence markedly declined in the recent decades. However, clinical features of CR patients now and the effect of reperfusion therapy to CR remain unclear. We investigated the clinical features of CR in STEMI patients and the effect of reperfusion therapy to CR in mice.

Methods: Two studies were conducted. In clinical study, data of 1456 STEMI patients admitted to the First Hospital, Xi'an Jiaotong University during 2015.12. ~ 2018.12. were analyzed. In experimental study, 83 male C57BL/6 mice were operated to induce MI. Of them, 39 mice were permanent MI (group-1), and remaining mice received reperfusion after 1 h ischemia (21 mice, group-2) or 4 h ischemia (23 mice, group-3). All operated mice were monitored up to day-10. Animals were inspected three times daily for the incidence of death and autopsy was done for all mice found died to determine the cause of death.

Results: CR was diagnosed in 40 patients: free-wall rupture in 17, ventricular septal rupture in 20, and combined locations in 3 cases. CR presented in 19 patients at admission and diagnosed in another 21 patients during 1 ~ 14 days post-STEMI, giving an in-hospital incidence of 1.4%. The mortality of CR patients was high during hospitalization accounting for 39% of total in-hospital death. By multivariate logistic regression analysis, older age, peak CK-MB and peak hs-CRP were independent predictors of CR post-STEMI. In mice with non-reperfused MI, 17 animals (43.6%) died of CR that occurred during 3-6 days post-MI. In MI mice received early or delayed reperfusion, all mice survived to the end of experiment except one mouse died of acute heart failure.

Conclusion: CR remains as a major cause of in-hospital death in STEMI patients. CR patients are characterized of being elderly, having larger infarct and more server inflammation. Experimentally, reperfusion post-MI prevented CR.
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http://dx.doi.org/10.1186/s12872-020-01683-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488297PMC
September 2020

Cardiac β-adrenergic receptor activation mediates distinct and cell type-dependent changes in the expression and distribution of connexin 43.

J Cell Mol Med 2020 08 24;24(15):8505-8517. Epub 2020 Jun 24.

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.

Activation of the sympatho-β-adrenergic receptors (β-ARs) system is a hallmark of heart failure, leading to fibrosis and arrhythmias. Connexin 43 (Cx43) is the most abundant gap junctional protein in the myocardium. Current knowledge is limited regarding Cx43 remodelling in diverse cell types in the diseased myocardium and the underlying mechanism. We studied cell type-dependent changes in Cx43 remodelling due to β-AR overactivation and molecular mechanisms involved. Mouse models of isoproterenol stimulation or transgenic cardiomyocyte overexpression of β -AR were used, which exhibited cardiac fibrosis and up-regulated total Cx43 abundance. In both models, whereas Cx43 expression in cardiomyocytes was reduced and more laterally distributed, fibroblasts exhibited elevated Cx43 expression and enhanced gap junction communication. Mechanistically, activation of β -AR in fibroblasts in vitro elevated Cx43 expression, which was abolished by the β -antagonist ICI-118551 or protein kinase A inhibitor H-89, but simulated by the adenylyl cyclase activator forskolin. Our in vitro and in vivo data showed that β-AR activation-induced production of IL-18 sequentially stimulated Cx43 expression in fibroblasts in a paracrine fashion. In summary, our findings demonstrate a pivotal role of β-AR in mediating distinct and cell type-dependent changes in the expression and distribution of Cx43, leading to pathological gap junction remodelling in the myocardium.
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http://dx.doi.org/10.1111/jcmm.15469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412418PMC
August 2020

Post-infarct left ventricular thrombosis is mechanistically related to ventricular wall rupture.

Med Hypotheses 2020 Nov 1;144:109938. Epub 2020 Jun 1.

Department of Physiology and Pathophysiology, College of Basic Medical Sciences, Xian Jiaotong University Health Science Center, Xian, China; Baker Heart and Diabetes Institute, Melbourne, Australia. Electronic address:

Left ventricular thrombus (LVT) after acute myocardial infarction (AMI) remains to be a common complication bearing adverse prognostic implication. Majority of LVT occurs within the first week after AMI. Over decades, the regional stasis of blood flow is regarded as the main reason for LVT formation. Here we hypothesize that LVT developed within the first week after AMI is the consequence of an incomplete wall rupture. Endocardial rupture with exposure of infarcted tissues triggers platelet thrombosis within the rupture site and then the thrombus grows towards the ventricular chamber forming LVT. This hypothesis is implicated by the comparable clinical features of patients with LVT or with cardiac rupture, and supported by experimental findings in murine model of AMI revealing the mechanistic link between rupture and LVT. This hypothesis, if confirmed, would improve our understanding on the pathophysiology of both rupture and LVT as two pivotal mechanical complications after AMI, and the role of platelets in the setting of AMI and hence the use of anti-platelet therapies. Future studies are warranted to test this hypothesis by serial cardiac imaging on AMI patients with high risk of LVT.
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http://dx.doi.org/10.1016/j.mehy.2020.109938DOI Listing
November 2020

Stretch-induced sarcoplasmic reticulum calcium leak is causatively associated with atrial fibrillation in pressure-overloaded hearts.

Cardiovasc Res 2021 Mar;117(4):1091-1102

The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, No. 28 West Xianning Road, Xi'an, Shaanxi 710049, China.

Aims: Despite numerous reports documenting an important role of hypertension in the development of atrial fibrillation (AF), the detailed mechanism underlying the pathological process remains incompletely understood. Here, we aim to test the hypothesis that diastolic sarcoplasmic reticulum (SR) Ca2+ leak in atrial myocytes, induced by mechanical stretch due to elevated pressure in the left atrium (LA), plays an essential role in the AF development in pressure-overloaded hearts.

Methods And Results: Isolated mouse atrial myocytes subjected to acute axial stretch displayed an immediate elevation of SR Ca2+ leak. Using a mouse model of transverse aortic constriction (TAC), the relation between stretch, SR Ca2+ leak, and AF susceptibility was further tested. At 36 h post-TAC, SR Ca2+ leak in cardiomyocytes from the LA (with haemodynamic stress), but not right atrium (without haemodynamic stress), significantly increased, which was further elevated at 4 weeks post-TAC. Accordingly, AF susceptibility to atrial burst pacing in the 4-week TAC mice were also significantly increased, which was unaffected by inhibition of atrial fibrosis or inflammation via deletion of galectin-3. Western blotting revealed that type 2 ryanodine receptor (RyR2) in left atrial myocytes of TAC mice was oxidized due to activation and up-regulation of Nox2 and Nox4. Direct rescue of dysfunctional RyR2 with dantrolene or rycal S107 reduced diastolic SR Ca2+ leak in left atrial myocytes and prevented atrial burst pacing stimulated AF.

Conclusion: Our study demonstrated for the first time the increased SR Ca2+ leak mediated by enhanced oxidative stress in left atrial myocytes that is causatively associated with higher AF susceptibility in pressure-overloaded hearts.
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http://dx.doi.org/10.1093/cvr/cvaa163DOI Listing
March 2021

Deficiency of Prebiotic Fiber and Insufficient Signaling Through Gut Metabolite-Sensing Receptors Leads to Cardiovascular Disease.

Circulation 2020 04 25;141(17):1393-1403. Epub 2020 Feb 25.

Heart Failure Research Group (D.M.K., W.A.S., H.A.J., D.H., B.G., A.F., F.Z.M.), Baker Heart and Diabetes Institute, Melbourne, Australia.

Background: High blood pressure (BP) continues to be a major, poorly controlled but modifiable risk factor for cardiovascular death. Among key Western lifestyle factors, a diet poor in fiber is associated with prevalence of high BP. The impact of lack of prebiotic fiber and the associated mechanisms that lead to higher BP are unknown. Here we show that lack of prebiotic dietary fiber leads to the development of a hypertensinogenic gut microbiota, hypertension and its complications, and demonstrate a role for G-protein coupled-receptors (GPCRs) that sense gut metabolites.

Methods: One hundred seventy-nine mice including C57BL/6J, gnotobiotic C57BL/6J, and knockout strains for GPR41, GPR43, GPR109A, and GPR43/109A were included. C57BL/6J mice were implanted with minipumps containing saline or a slow-pressor dose of angiotensin II (0.25 mg·kg·d). Mice were fed diets lacking prebiotic fiber with or without addition of gut metabolites called short-chain fatty acids ([SCFA)] produced during fermentation of prebiotic fiber in the large intestine), or high prebiotic fiber diets. Cardiac histology and function, BP, sodium and potassium excretion, gut microbiome, flow cytometry, catecholamines and methylation-wide changes were determined.

Results: Lack of prebiotic fiber predisposed mice to hypertension in the presence of a mild hypertensive stimulus, with resultant pathological cardiac remodeling. Transfer of a hypertensinogenic microbiota to gnotobiotic mice recapitulated the prebiotic-deprived hypertensive phenotype, including cardiac manifestations. Reintroduction of SCFAs to fiber-depleted mice had protective effects on the development of hypertension, cardiac hypertrophy, and fibrosis. The cardioprotective effect of SCFAs were mediated via the cognate SCFA receptors GPR43/GPR109A, and modulated L-3,4-dihydroxyphenylalanine levels and the abundance of T regulatory cells regulated by DNA methylation.

Conclusions: The detrimental effects of low fiber Westernized diets may underlie hypertension, through deficient SCFA production and GPR43/109A signaling. Maintaining a healthy, SCFA-producing microbiota is important for cardiovascular health.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043081DOI Listing
April 2020

Association between heart rate variability indices and features of spontaneous ventricular tachyarrhythmias in mice.

Clin Exp Pharmacol Physiol 2020 07 28;47(7):1193-1202. Epub 2020 Feb 28.

Experimental Cardiology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Vic, Australia.

Direct evidence is limited for the association between heart rate variability (HRV) indices and ventricular tachyarrhythmias (VTAs). While galectin-3 (Gal-3) is regarded as a causal factor for cardiac remodelling and a biomarker for arrhythmias, its regulation on VTAs and HVR is unknown. Using aged transgenic (TG) mice with cardiac overexpression of β -adrenoceptors and spontaneous VTAs, we studied whether changes in HRV indices correlated with the severity of VTAs, and whether Gal-3 gene knockout (KO) in TG mice might limit VTA. Body-surface ECG was recorded (10-minute period) in 9- to 10-month-old mice of non-transgenic (nTG), TG and TG × Gal-3 knockout (TG/KO). Time-domain, frequency-domain and nonlinear-domain HRV indices were calculated using the R-R intervals extracted from ECG signals and compared with frequency of VTAs. TG and TG/KO mice developed frequent VTAs and showed significant changes in certain time-domain and nonlinear-domain HRV indices relative to nTG mice. The severity of VTAs in TG and TG/KO mice in combination, estimated by VTA counts and arrhythmia score, was significantly correlated with certain time-domain and nonlinear-domain HRV indices. In conclusion, significant changes in HRV indices were evident and correlated with the severity of spontaneous VTAs in TG mice. The frequency of VTA and HRV indices were largely comparable between TG and TG/KO mice. Deletion of Gal-3 in TG mice altered certain HRV indices implying influence by neuronally localized Gal-3 on autonomic nervous activity.
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http://dx.doi.org/10.1111/1440-1681.13275DOI Listing
July 2020

Gal-3 (Galectin-3) and K3.1 Mediate Heterogeneous Cell Coupling and Myocardial Fibrogenesis Driven by βAR (β-Adrenoceptor) Activation.

Hypertension 2020 02 16;75(2):393-404. Epub 2019 Dec 16.

From the Department of Physiology and Pathophysiology (G.S., M.-C.H., Yu Zhang, Yi Zhang, Y.W., X.-J.D., X.-L.D.), Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.

Heart failure is associated with sympatho-βAR (β-adrenoceptor) activation and cardiac fibrosis. Gal-3 (galectin-3) and K3.1 channels that are upregulated in diverse cells of diseased heart are implicated in mediating myocardial inflammation and fibrosis. It remains unclear whether Gal-3 interacts with K3.1 leading to cardiac fibrosis in the setting of βAR activation. We tested the effect of K3.1 blocker TRAM-34 on cardiac fibrosis and inflammation in cardiac-restricted β-TG (βAR overexpressed transgenic) mice and determined K3.1 expression in β-TG×Gal-3 mouse hearts. Mechanisms of K3.1 in mediating Gal-3 induced fibroblast activation were studied ex vivo. Expression of Gal-3 and K3.1 was elevated in β-TG hearts. gene deletion in β-TG mice decreased K3.1 expression in inflammatory cells but not in fibroblasts. Treatment of β-TG mice with TRAM-34 for 1 or 2 months significantly ameliorated cardiac inflammation and fibrosis and reduced Gal-3 level. In cultured fibroblasts, Gal-3 upregulated K3.1 expression and channel currents with enhanced membrane potential and Ca entry through TRPV4 (transient receptor potential V4) and TRPC6 (transient receptor potential C6) channels leading to fibroblast activation. In conclusion, βAR stimulation promotes Gal-3 production that upregulates K3.1 channels in noncardiomyocyte cells and activates K3.1 channels in fibroblasts leading to hyperpolarization of membrane potential and Ca entry via TRP channels. Gal-3-K3.1 signaling mobilizes diverse cells facilitating regional inflammation and fibroblast activation and hence myocardial fibrosis.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13696DOI Listing
February 2020

K3.1 channel mediates inflammatory signaling of pancreatic β cells and progression of type 2 diabetes mellitus.

FASEB J 2019 12 5;33(12):14760-14771. Epub 2019 Nov 5.

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.

Chronic islet inflammation is associated with development of type 2 diabetes mellitus (T2DM). Intermediate-conductance calcium-activated K (K3.1) channel plays an important role in inflammatory diseases. However, the role and regulation of K3.1 in pancreatic β cells in progression of T2DM remain unclarified. In the present study, we evaluated the effect of the specific K3.1 channel blocker 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34) on diabetic phenotype in the db/db model. In diabetic mice, blockade of K3.1 significantly improved glucose tolerance, enhanced secretion of postprandial insulin level, and reduced loss of β-cell mass through attenuating the expression and secretion of inflammatory mediators. Furthermore, in cultured pancreatic β cells, exposure to high levels of glucose or palmitic acid significantly increased expression and current density of the K3.1 channel as well as secretion of proinflammatory chemokines, and the effects were similarly reversed by preincubation with TRAM-34 or a NF-κB inhibitor pyrrolidinedithiocarbamate. Additionally, expression of K3.1 in pancreas islet cells was up-regulated by activation of NF-κB with IL-1β stimulation. In summary, up-regulated K3.1 due to activation of NF-κB pathway leads to pancreatic inflammation expression and secretion of chemokines and cytokines by pancreatic β cells, thereby facilitating progression of T2DM.-Pang, Z.-D., Wang, Y., Wang, X.-J., She, G., Ma, X.-Z., Song, Z., Zhao, L.-M., Wang, H.-F., Lai, B.-C., Gou, W., Du, X.-J., Deng, X.-L. K3.1 channel mediates inflammatory signaling of pancreatic β cells and progression of type 2 diabetes mellitus.
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http://dx.doi.org/10.1096/fj.201901329RRDOI Listing
December 2019

Circulating MIF Levels Predict Clinical Outcomes in Patients With ST-Elevation Myocardial Infarction After Percutaneous Coronary Intervention.

Can J Cardiol 2019 10 21;35(10):1366-1376. Epub 2019 May 21.

State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Cardiovascular Disease Research, Clinical Medical Research Institute of First Affiliated Hospital of Xinjiang Medical University, Urumqi, China. Electronic address:

Background: The purpose of the study was to assess the value of admission macrophage migration inhibitory factor (MIF) levels in predicting clinical outcomes in ST-elevation myocardial infarction (STEMI) patients.

Methods: For this study we recruited 498 STEMI patients after they received percutaneous coronary intervention (PCI), 40 with stable angina pectoris and 137 healthy participants. Plasma MIF levels were measured at admission and after PCI. The primary end points were in-hospital mortality and major adverse cardio-and/or cerebrovascular events (MACCE) during hospitalization and 3.2-year follow-up period.

Results: Admission MIF levels were elevated in 88.4% of STEMI patients over the upper reference limit of healthy controls and it was 3- to 7-fold higher than that in stable angina pectoris and control groups (122 ± 61 vs 39 ± 19 vs 17 ± 8 ng/mL; P < 0.001). Admission MIF levels were significantly higher in patients who died after myocardial infarction vs survivors. For predicting in-hospital mortality using the optimal cutoff value (127.8 ng/mL) of MIF, the area under the receiver operating characteristic curve for MIF was 0.820, similar area under the receiver operating characteristic curve values for predicting short-term outcomes were observed for high-sensitivity troponin T, CK-MB, N-terminal probrain natriuretic peptide, and Global Registry of Acute Coronary Events (GRACE) score. Although peak high-sensitivity troponin T and N-terminal probrain natriuretic peptide also predicted MACCE during the follow-up period, only higher admission MIF levels predicted in-hospital mortality and MACCE during the 3.2-year follow-up. Multivariate regression analysis showed the independent predictive value of a higher admission MIF level (≥ 127.8 ng/mL) on in-hospital mortality (odds ratio, 9.1; 95% confidence interval, 1.7-47.2) and 3.2-year MACCE (hazard ratio, 2.8; 95% confidence interval, 1.5-5.6).

Conclusions: A higher admission MIF level is an independent predictor for in-hospital mortality and long-term MACCE in STEMI patients who underwent PCI.
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http://dx.doi.org/10.1016/j.cjca.2019.04.028DOI Listing
October 2019

Oxidative stress induced by palmitic acid modulates K2.3 channels in vascular endothelium.

Exp Cell Res 2019 10 12;383(2):111552. Epub 2019 Aug 12.

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, 710061, Shaanxi, China; Cardiovascular Research Centre, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, 710061, Shaanxi, China. Electronic address:

Elevated plasma free fatty acids level has been implicated in the development of insulin resistance, inflammation, and endothelial dysfunction in diabetic and nondiabetic individuals. However, the underlying mechanisms still remain to be defined. Herein, we investigated the effect of palmitic acid (PA), the most abundant saturated fatty acid in the human body, on small-conductance Ca-activated potassium channels (K2.3)-mediated relaxation in rodent resistance arteries and the underlying molecular mechanism. The effect of PA on K2.3 in endothelium was evaluated using real-time PCR, Western blotting, whole-cell patch voltage-clamp, wire and pressure myograph system, and reactive oxygen species (ROS) were measured by using dihydroethidium and 2', 7'-dichlorofluorescein diacetate. K2.3-mediated vasodilatation responses to acetylcholine and NS309 (agonist of K2.3 and K3.1) were impaired by incubation of normal mesenteric arteries with 100 μM PA for 24 h. In cultured human umbilical vein endothelial cells (HUVECs), PA decreased K2.3 current and expression at mRNA and protein levels. Incubation with the NADPH oxidase (Nox) inhibitor dibenziodolium (DPI) partly inhibited the PA-induced ROS production and restored K2.3 expression. Inhibition of either p38-MAPK or NF-κB using specific inhibitors (SB203580, SB202190 or Bay11-7082, pyrrolidinedithiocarbamate) attenuated PA-induced downregulation of K2.3 and inhibition of p38-MAPK also attenuated PA-induced phosphorylation of NF-κB p65. Furthermore, DPI reversed the increment of phospho-p38-MAPK by PA. These results demonstrated that PA downregulated K2.3 expressions via Nox/ROS/p38-MAPK/NF-κB signaling leading to endothelial vasodilatory dysfunction.
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http://dx.doi.org/10.1016/j.yexcr.2019.111552DOI Listing
October 2019

Sex-Based Mhrt Methylation Chromatinizes MeCP2 in the Heart.

iScience 2019 Jul 27;17:288-301. Epub 2019 Jun 27.

Epigenetics in Human Health and Disease, Central Clinical School, Faculty of Medicine, Monash University, Melbourne, VIC 3004, Australia; Baker Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, VIC 3004, Australia; Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3010, Australia; Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, The Chinese University of Hong Kong, 3/F Lui Che Woo Clinical Sciences Building, 30-32 Ngan Shing Street, Sha Tin, Hong Kong SAR; University College Copenhagen, Faculty of Health, Department of Technology, Biomedical Laboratory Science, Copenhagen, Denmark. Electronic address:

In the heart, primary microRNA-208b (pri-miR-208b) and Myheart (Mhrt) are long non-coding RNAs (lncRNAs) encoded by the cardiac myosin heavy chain genes. Although preclinical studies have shown that lncRNAs regulate gene expression and are protective for pathological hypertrophy, the mechanism underlying sex-based differences remains poorly understood. In this study, we examined DNA- and RNA-methylation-dependent regulation of pri-miR-208b and Mhrt. Expression of pri-miR-208b is elevated in the left ventricle of the female heart. Despite indistinguishable DNA methylation between sexes, the interaction of MeCP2 on chromatin is subject to RNase digestion, highlighting that affinity of the methyl-CG reader is broader than previously thought. A specialized procedure to isolate RNA from soluble cardiac chromatin emphasizes sex-based affinity of an MeCP2 co-repressor complex with Rest and Hdac2. Sex-specific Mhrt methylation chromatinizes MeCP2 at the pri-miR-208b promoter and extends the functional relevance of default transcriptional suppression in the heart.
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http://dx.doi.org/10.1016/j.isci.2019.06.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639684PMC
July 2019

Relaxin mitigates microvascular damage and inflammation following cardiac ischemia-reperfusion.

Basic Res Cardiol 2019 06 19;114(4):30. Epub 2019 Jun 19.

Experimental Cardiology Laboratory, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, 3004, Australia.

Microvascular obstruction (MVO) and leakage (MVL) forms a pivotal part of microvascular damage following cardiac ischemia-reperfusion (IR). We tested the effect of relaxin therapy on MVO and MVL in mice following cardiac IR injury including severity of MVO and MVL, opening capillaries, infarct size, regional inflammation, cardiac function and remodelling, and permeability of cultured endothelial monolayer. Compared to vehicle group, relaxin treatment (50 μg/kg) reduced no-reflow area by 38% and the content of Evans blue as a permeability tracer by 56% in jeopardized myocardium (both P < 0.05), effects associated with increased opening capillaries. Relaxin also decreased leukocyte density, gene expression of cytokines, and mitigated IR-induced decrease in protein content of VE-cadherin and relaxin receptor. Infarct size was comparable between the two groups. At 2 weeks post-IR, relaxin treatment partially preserved cardiac contractile function and limited chamber dilatation versus untreated controls by echocardiography. Endothelial cell permeability assay demonstrated that relaxin attenuated leakage induced by hypoxia-reoxygenation, HO, or cytokines, action that was independent of nitric oxide but associated with the preservation of VE-cadherin. In conclusion, relaxin therapy attenuates IR-induced MVO and MVL and endothelial leakage. This protection was associated with reduced regional inflammatory responses and consequently led to alleviated adverse cardiac remodeling.
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http://dx.doi.org/10.1007/s00395-019-0739-9DOI Listing
June 2019

Reply to "Letter to the Editor: Not all modified citrus pectins are the same: size does matter".

Am J Physiol Heart Circ Physiol 2019 05;316(5):H1234-H1235

Experimental Cardiology Laboratory, Baker Heart and Diabetes Institute , Melbourne , Australia.

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http://dx.doi.org/10.1152/ajpheart.00197.2019DOI Listing
May 2019

Cardioprotective Actions of the Annexin-A1 N-Terminal Peptide, Ac, Against Myocardial Infarction.

Front Pharmacol 2019 3;10:269. Epub 2019 Apr 3.

Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.

The anti-inflammatory, pro-resolving annexin-A1 protein acts as an endogenous brake against exaggerated cardiac necrosis, inflammation, and fibrosis following myocardial infarction (MI) . Little is known, however, regarding the cardioprotective actions of the N-terminal-derived peptide of annexin A1, Ac, particularly beyond its anti-necrotic actions in the first few hours after an ischemic insult. In this study, we tested the hypothesis that exogenous Ac limits cardiac injury and Firstly, we demonstrated that Ac limits cardiomyocyte death both and in mice subjected to ischemia-reperfusion (I-R) injury (Ac 1 mg/kg, i.v. just prior to post-ischemic reperfusion). Further, Ac (1 mg/kg i.v.) reduced cardiac inflammation (after 48 h reperfusion), as well as both cardiac fibrosis and apoptosis (after 7-days reperfusion). Lastly, we investigated whether Ac preserved cardiac function after MI. Ac (1 mg/kg/day s.c., osmotic pump) delayed early cardiac dysfunction 1 week post MI, but elicited no further improvement 4 weeks after MI. Taken together, our data demonstrate the first evidence that Ac not only preserves cardiomyocyte survival , but also offers cardioprotection beyond the first few hours after an ischemic insult . Annexin-A1 mimetics thus represent a potential new therapy to improve cardiac outcomes after MI.
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http://dx.doi.org/10.3389/fphar.2019.00269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457169PMC
April 2019

Stimulation of β-adrenoceptors up-regulates cardiac expression of galectin-3 and BIM through the Hippo signalling pathway.

Br J Pharmacol 2019 07 30;176(14):2465-2481. Epub 2019 May 30.

Experimental Cardiology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.

Background And Purpose: Expression of the pro-fibrotic galectin-3 and the pro-apoptotic BIM is elevated in diseased heart or after β-adrenoceptor stimulation, but the underlying mechanisms are unclear. This question was addressed in the present study.

Experimental Approach: Wild-type mice and mice with cardiac transgenic expression of β -adrenoceptors, mammalian sterile-20 like kinase 1 (Mst1) or dominant-negative Mst1, and non-specific galectin-3 knockout mice were used. Effects of the β-adrenoceptor agonist isoprenaline or β-adrenoceptor antagonists were studied. Rat cardiomyoblasts (H9c2) were used for mechanistic exploration. Biochemical assays were performed.

Key Results: Isoprenaline treatment up-regulated expression of galectin-3 and BIM, and this was inhibited by non-selective or selective β-adrenoceptor antagonists (by 60-70%). Cardiac expression of galectin-3 and BIM was increased in β -adrenoceptor transgenic mice. Isoprenaline-induced up-regulation of galectin-3 and BIM was attenuated by Mst1 inactivation, but isoprenaline-induced galectin-3 expression was exaggerated by transgenic Mst1 activation. Pharmacological or genetic activation of β-adrenoceptors induced Mst1 expression and yes-associated protein (YAP) phosphorylation. YAP hyper-phosphorylation was also evident in Mst1 transgenic hearts with up-regulated expression of galectin-3 (40-fold) and BIM as well as up-regulation of many YAP-target genes by RNA sequencing. In H9c2 cells, isoprenaline induced YAP phosphorylation and expression of galectin-3 and BIM, effects simulated by forskolin but abolished by PKA inhibitors, and YAP knockdown induced expression of galectin-3 and BIM.

Conclusions And Implications: Stimulation of cardiac β-adrenoceptors activated the Mst1/Hippo pathway leading to YAP hyper-phosphorylation with enhanced expression of galectin-3 and BIM. This signalling pathway would have therapeutic potential.

Linked Articles: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.
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http://dx.doi.org/10.1111/bph.14674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592853PMC
July 2019

Macrophage migration inhibitory factor plays an essential role in ischemic preconditioning-mediated cardioprotection.

Clin Sci (Lond) 2019 03 5;133(5):665-680. Epub 2019 Mar 5.

Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China

Ischemic preconditioning (IPC) is an endogenous protection strategy against myocardial ischemia-reperfusion (I/R) injury. Macrophage migration inhibitory factor (MIF) released from the myocardium subjected to brief periods of ischemia confers cardioprotection. We hypothesized that MIF plays an essential role in IPC-induced cardioprotection. I/R was induced either or in male wild-type (WT) and MIF knockout (MIFKO) mice with or without proceeding IPC (three cycles of 5-min ischemia and 5-min reperfusion). Indices of myocardial injury, regional inflammation and cardiac function were determined to evaluate the extent of I/R injury. Activations of the reperfusion injury salvage kinase (RISK) pathway, AMP-activated protein kinase (AMPK) and their downstream components were investigated to explore the underlying mechanisms. IPC conferred prominent protection in WT hearts evidenced by reduced infarct size (by 33-35%), myocyte apoptosis and enzymatic markers of tissue injury, ROS production, inflammatory cell infiltration and MCP1/CCR2 expression (all <0.05). IPC also ameliorated cardiac dysfunction both and These protective effects were abolished in MIFKO hearts. Notably, IPC mediated further activations of RISK pathway, AMPK and the membrane translocation of GLUT4 in WT hearts. Deletion of MIF blunted these changes in response to IPC, which is the likely basis for the absence of protective effects of IPC against I/R injury. In conclusion, MIF plays a critical role in IPC-mediated cardioprotection under ischemic stress by activating RISK signaling pathway and AMPK. These results provide an insight for developing a novel therapeutic strategy that target MIF to protect ischemic hearts.
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http://dx.doi.org/10.1042/CS20181013DOI Listing
March 2019

β-Adrenoceptor activation affects galectin-3 as a biomarker and therapeutic target in heart disease.

Br J Pharmacol 2019 07 7;176(14):2449-2464. Epub 2019 Apr 7.

Experimental Cardiology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.

Myocardial fibrosis is a key histopathological component that drives the progression of heart disease leading to heart failure and constitutes a therapeutic target. Recent preclinical and clinical studies have implicated galectin-3 (Gal-3) as a pro-fibrotic molecule and a biomarker of heart disease and fibrosis. However, our knowledge is poor on the mechanism(s) that determine the blood level or regulate cardiac expression of Gal-3. Recent studies have demonstrated that enhanced β-adrenoceptor activity is a determinant of both circulating concentration and cardiac expression of Gal-3. Pharmacological or transgenic activation of β-adrenoceptors leads to increased blood levels of Gal-3 and up-regulated cardiac Gal-3 expression, effect that can be reversed with the use of β-adrenoceptor antagonists. Conversely, Gal-3 gene deletion confers protection against isoprenaline-induced cardiotoxicity and fibrogenesis. At the transcription level, β-adrenoceptor stimulation activates cardiac mammalian sterile-20-like kinase 1, a pivotal kinase of the Hippo signalling pathway, which is associated with Gal-3 up-regulation. Recent studies have suggested a role for the β-adrenoceptor-Hippo signalling pathway in the regulation of cardiac Gal-3 expression thereby contributing to the onset and progression of heart disease. This implies a therapeutic potential of the suppression of Gal-3 expression. In this review, we discuss the effects of β-adrenoceptor activity on Gal-3 as a biomarker and causative mediator in the setting of heart disease and point out pivotal knowledge gaps. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.
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http://dx.doi.org/10.1111/bph.14620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592856PMC
July 2019

Towards better definition, quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association (HFA) of the European Society of Cardiology.

Eur J Heart Fail 2019 03 4;21(3):272-285. Epub 2019 Feb 4.

Department of Cardiology, CARIM School for Cardiovascular Diseases Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.

Fibrosis is a pivotal player in heart failure development and progression. Measurements of (markers of) fibrosis in tissue and blood may help to diagnose and risk stratify patients with heart failure, and its treatment may be effective in preventing heart failure and its progression. A lack of pathophysiological insights and uniform definitions has hampered the research in fibrosis and heart failure. The Translational Research Committee of the Heart Failure Association discussed several aspects of fibrosis in their workshop. Early insidious perturbations such as subclinical hypertension or inflammation may trigger first fibrotic events, while more dramatic triggers such as myocardial infarction and myocarditis give rise to full blown scar formation and ongoing fibrosis in diseased hearts. Aging itself is also associated with a cardiac phenotype that includes fibrosis. Fibrosis is an extremely heterogeneous phenomenon, as several stages of the fibrotic process exist, each with different fibrosis subtypes and a different composition of various cells and proteins - resulting in a very complex pathophysiology. As a result, detection of fibrosis, e.g. using current cardiac imaging modalities or plasma biomarkers, will detect only specific subforms of fibrosis, but cannot capture all aspects of the complex fibrotic process. Furthermore, several anti-fibrotic therapies are under investigation, but such therapies generally target aspecific aspects of the fibrotic process and suffer from a lack of precision. This review discusses the mechanisms and the caveats and proposes a roadmap for future research.
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http://dx.doi.org/10.1002/ejhf.1406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607480PMC
March 2019

K3.1 Channels Promote Cardiac Fibrosis Through Mediating Inflammation and Differentiation of Monocytes Into Myofibroblasts in Angiotensin II -Treated Rats.

J Am Heart Assoc 2019 01;8(1):e010418

1 Department of Physiology and Pathophysiology School of Basic Medical Sciences Xi'an Jiaotong University Health Science Center Xi'an Shaanxi China.

Background Cardiac fibrosis is a core pathological process associated with heart failure. The recruitment and differentiation of primitive fibroblast precursor cells of bone marrow origin play a critical role in pathological interstitial cardiac fibrosis. The K 3.1 channels are expressed in both ventricular fibroblasts and circulating mononuclear cells in rats and are upregulated by angiotensin II . We hypothesized that K 3.1 channels mediate the inflammatory microenvironment in the heart, promoting the infiltrated bone marrow-derived circulating mononuclear cells to differentiate into myofibroblasts, leading to myocardial fibrosis. Methods and Results We established a cardiac fibrosis model in rats by infusing angiotensin II to evaluate the impact of the specific K 3.1 channel blocker TRAM -34 on cardiac fibrosis. At the same time, mouse CD 4 T cells and rat circulating mononuclear cells were separated to investigate the underlying mechanism of the TRAM -34 anti-cardiac fibrosis effect. TRAM -34 significantly attenuated cardiac fibrosis and the inflammatory reaction and reduced the number of fibroblast precursor cells and myofibroblasts. Inhibition of K 3.1 channels suppressed angiotensin II -stimulated expression and secretion of interleukin-4 and interleukin-13 in CD 4 T cells and interleukin-4- or interleukin-13-induced differentiation of monocytes into fibrocytes. Conclusions K 3.1 channels facilitate myocardial inflammation and the differentiation of bone marrow-derived monocytes into myofibroblasts in cardiac fibrosis caused by angiotensin II infusion.
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http://dx.doi.org/10.1161/JAHA.118.010418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405723PMC
January 2019

Galectin-3 deficiency ameliorates fibrosis and remodeling in dilated cardiomyopathy mice with enhanced Mst1 signaling.

Am J Physiol Heart Circ Physiol 2019 01 2;316(1):H45-H60. Epub 2018 Nov 2.

Baker Heart and Diabetes Institute , Melbourne, Victoria , Australia.

Dilated cardiomyopathy (DCM) is a major cause of heart failure without effective therapy. Fibrogenesis plays a key role in the development of DCM, but little is known of the expression of the profibrotic factor galectin-3 (Gal-3) and its role in DCM pathophysiology. In a mouse DCM model with transgenic (TG) overexpression of mammalian sterile 20-like kinase 1 (Mst1), we studied Gal-3 expression and effects of the Gal-3 inhibitor modified citrus pectin (MCP) or Gal-3 gene knockout (KO). Gal-3 deletion in TG mice (TG/KO) was achieved by crossbreeding Mst1-TG mice with Gal-3 KO mice. The DCM phenotype was assessed by echocardiography and micromanometry. Cardiac expression of Gal-3 and fibrosis were determined. The cardiac transcriptome was profiled by RNA sequencing. Mst1-TG mice at 3-8 mo of age exhibited upregulated expression of Gal-3 by ~40-fold. TG mice had dilatation of cardiac chambers, suppressed left ventricular (LV) ejection fraction, poor LV contractility and relaxation, a threefold increase in LV collagen content, and upregulated fibrotic genes. Four-month treatment with MCP showed no beneficial effects. Gal-3 deletion in Mst1-TG mice attenuated chamber dilatation, organ congestion, and fibrogenesis. RNA sequencing identified profound disturbances by Mst1 overexpression in the cardiac transcriptome, which largely remained in TG/KO hearts. Gal-3 deletion in Mst1-TG mice, however, partially reversed the dysregulated transcriptional signaling involving extracellular matrix remodeling and collagen formation. We conclude that cardiac Mst1 activation leads to marked Gal-3 upregulation and transcriptome disturbances in the heart. Gal-3 deficiency attenuated cardiac remodeling and fibrotic signaling. NEW & NOTEWORTHY We found in a transgenic mouse dilated cardiomyopathy (DCM) model a pronounced upregulation of galectin-3 in cardiomyocytes. Galectin-3 gene deletion reduced cardiac fibrosis and fibrotic gene profiles and ameliorated cardiac remodeling and dysfunction. These benefits of galectin-3 deletion were in contrast to the lack of effect of treatment with the galectin-3 inhibitor modified citrus pectin. Our study suggests that suppression of galectin-3 mRNA expression could be used to treat DCM with high cardiac galectin-3 content.
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http://dx.doi.org/10.1152/ajpheart.00609.2018DOI Listing
January 2019

Serelaxin attenuates renal inflammation and fibrosis in a mouse model of dilated cardiomyopathy.

Exp Physiol 2018 12 5;103(12):1593-1602. Epub 2018 Nov 5.

Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.

New Findings: What is the central question of this study? The aim was to determine the renoprotective effects of serelaxin in the setting of chronic heart failure. What are the main findings and its importance? Our data indicate that serelaxin can reduce renal fibrosis and inflammation in experimental heart failure. Currently, there are no effective treatments to rescue renal function in heart failure patients, and our data suggest that serelaxin might have the potential to reduce renal fibrosis and inflammation in heart failure.

Abstract: Serelaxin has been demonstrated to attenuate renal fibrosis and inflammation in cardiorenal disease. In the present study, we tested the hypothesis that serelaxin can prevent the decline in renal function in dilated cardiomyopathy (DCM) by targeting renal fibrosis and inflammation. Male transgenic mice with DCM (n = 16) and their wild-type littermates (WT; n = 20) were administered either vehicle or serelaxin (500 μg kg  day ; subcutaneous minipumps; 8 weeks). Cardiac function was assessed via echocardiography before and during the eighth week of serelaxin treatment. Renal function and inflammation as well as cardiac and renal fibrosis were assessed at the end of the study. Serelaxin had minimal effect on cardiac function (P ≥ 0.99). Tubulointerstitial and glomerular fibrosis were ∼3-fold greater in vehicle-treated DCM mice compared with vehicle-treated WT mice (P ≤ 0.001). Renal mRNA expression of Tnfα and Il1α were ∼4- and ∼3-fold greater, respectively, in vehicle-treated DCM mice compared with vehicle-treated WT mice (P ≤ 0.05). Tubulointerstitial and glomerular fibrosis were 46 and 45% less, respectively, in serelaxin-treated DCM mice than in vehicle-treated DCM mice (P ≤ 0.01). Renal cortical mRNA expression of Tnfα and Il1α were 56 and 58% less, respectively, in the former group compared with the latter (P ≤ 0.05). The urinary albumin:creatinine ratio was ∼3-fold greater in vehicle-treated DCM mice compared with vehicle-treated WT mice (P = 0.02). The urinary albumin:creatinine ratio was not significantly different between vehicle-treated DCM mice and serelaxin-treated DCM mice (P = 0.38). These data suggest that serelaxin can attenuate renal fibrosis and inflammation and has the potential to exert renoprotective effects in DCM.
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http://dx.doi.org/10.1113/EP087189DOI Listing
December 2018

Age-Related Differential Structural and Transcriptomic Responses in the Hypertensive Heart.

Front Physiol 2018 9;9:817. Epub 2018 Jul 9.

Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.

While aging is a critical risk factor for heart failure, it remains uncertain whether the aging heart responds differentially to a hypertensive stimuli. Here we investigated phenotypic and transcriptomic differences between the young and aging heart using a mineralocorticoid-excess model of hypertension. Ten-week ("young") and 36-week ("aging") mice underwent a unilateral uninephrectomy with deoxycorticosterone acetate (DOCA) pellet implantation ( = 6-8/group) and were followed for 6 weeks. Cardiac structure and function, blood pressure (BP) and the cardiac transcriptome were subsequently examined. Young and aging DOCA mice had high BP, increased cardiac mass, cardiac hypertrophy, and fibrosis. Left ventricular end-diastolic pressure increased in aging DOCA-treated mice in contrast to young DOCA mice. Interstitial and perivascular fibrosis occurred in response to DOCA, but perivascular fibrosis was greater in aging mice. Transcriptomic analysis showed that young mice had features of higher oxidative stress, likely due to activation of the respiratory electron transport chain. In contrast, aging mice showed up-regulation of collagen formation in association with activation of innate immunity together with markers of inflammation including cytokine and platelet signaling. In comparison to younger mice, aging mice demonstrated different phenotypic and molecular responses to hypertensive stress. These findings have potential implications for the pathogenesis of age-related forms of cardiovascular disease, particularly heart failure.
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http://dx.doi.org/10.3389/fphys.2018.00817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046461PMC
July 2018

Mechanisms responsible for increased circulating levels of galectin-3 in cardiomyopathy and heart failure.

Sci Rep 2018 05 29;8(1):8213. Epub 2018 May 29.

Baker Heart and Diabetes Institute, Melbourne, Australia.

Galectin-3 is a biomarker of heart disease. However, it remains unknown whether increase in galectin-3 levels is dependent on aetiology or disease-associated conditions and whether diseased heart releases galectin-3 into the circulation. We explored these questions in mouse models of heart disease and in patients with cardiomyopathy. All mouse models (dilated cardiomyopathy, DCM; fibrotic cardiomyopathy, ischemia-reperfusion, I/R; treatment with β-adrenergic agonist isoproterenol) showed multi-fold increases in cardiac galectin-3 expression and preserved renal function. In mice with fibrotic cardiomyopathy, I/R or isoproterenol treatment, plasma galectin-3 levels and density of cardiac inflammatory cells were elevated. These models also exhibited parallel changes in cardiac and plasma galectin-3 levels and presence of trans-cardiac galectin-3 gradient, indicating cardiac release of galectin-3. DCM mice showed no change in circulating galectin-3 levels nor trans-cardiac galectin-3 gradient or myocardial inflammatory infiltration despite a 50-fold increase in cardiac galectin-3 content. In patients with hypertrophic cardiomyopathy or DCM, plasma galectin-3 increased only in those with renal dysfunction and a trans-cardiac galectin-3 gradient was not present. Collectively, this study documents the aetiology-dependency and diverse mechanisms of increment in circulating galectin-3 levels. Our findings highlight cardiac inflammation and enhanced β-adrenoceptor activation in mediating elevated galectin-3 levels via cardiac release in the mechanism.
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http://dx.doi.org/10.1038/s41598-018-26115-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973942PMC
May 2018

The role and mechanism of K3.1 channels in human monocyte migration induced by palmitic acid.

Exp Cell Res 2018 08 21;369(2):208-217. Epub 2018 May 21.

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an 710061, Shaanxi, China; Cardiovascular Research Centre, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an 710061, Shaanxi, China. Electronic address:

Monocyte migration into diseased tissues contributes to the pathogenesis of diseases. Intermediate-conductance Ca-activated K (K3.1) channels play an important role in cell migration. However, the role of K3.1 channels in mediating monocyte migration induced by palmitic acid (PA) is still unclear. Using cultured THP-1 cells and peripheral blood mononuclear cells from healthy subjects, we investigated the role and signaling mechanisms of K3.1 channels in mediating the migration induced by PA. Using methods of Western blotting analysis, RNA interference, cell migration assay and ELISA, we found that PA-treated monocytes exhibited increment of the protein levels of K3.1 channel and monocyte chemoattractant protein-1 (MCP-1), and the effects were reversed by co-incubation of PA with anti-TLR2/4 antibodies or by specific inhibitors of p38-MAPK, or NF-κB. In addition, PA increased monocyte migration, which was abolished by a specific K3.1 channel blocker, TRAM-34, or K3.1 small interfering RNA (siRNA). The expression and secretion of MCP-1 induced by PA was also similarly prevented by TRAM-34 and K3.1 siRNA. These results demonstrate for the first time that PA upregulates K3.1 channels through TLR2/4, p38-MAPK and NF-κB pathway to promote the expression of MCP-1, and then induce the trans-endothelial migration of monocytes.
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http://dx.doi.org/10.1016/j.yexcr.2018.05.020DOI Listing
August 2018

Admission macrophage migration inhibitory factor predicts long-term prognosis in patients with ST-elevation myocardial infarction.

Eur Heart J Qual Care Clin Outcomes 2018 07;4(3):208-219

Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, 49 Hua Yuan Bei Lu, Hai Dian District, Beijing, China.

Aims: We previously showed in patients with ST-segment elevated myocardial infarction (STEMI) that admission levels of macrophage migration inhibitory factor (MIF) predict infarct size. We studied whether admission MIF alone or in combination with other biomarkers is useful for risk assessment of acute and chronic clinical outcomes in STEMI patients.

Methods And Results: A total of 658 STEMI patients treated with primary percutaneous coronary intervention (PCI) were consecutively recruited. MIF level was determined at admission and echocardiography performed on day-3 and then 12 months post-MI. Patients were followed for a median period of 64 months. Major endpoints included ST-segment resolution, all-cause mortality, and major adverse cardiovascular events (MACE). High MIF level was associated with larger enzymatic infarct size, incomplete resolution of ST-segment elevation post-PCI, impaired left ventricular ejection fraction (LVEF), and poorer improvement of LVEF (all P < 0.001). After adjustment for classical risk factors standard biomarkers and day-3 LVEF, admission MIF remained independently prognostic for all-cause mortality [hazard ratio (HR) 2.27, 95% confidence interval (CI) 1.43-3.22], and MACE (HR 1.39, 95% CI 1.12-1.71, both P < 0.05). MIF was a significant additive predictor of all-cause mortality with a net reclassification improvement of 0.34 (P = 0.02). Furthermore, patients in high tertile of both admission MIF and day-3 Nt-proBNP had the highest mortality risk relative to other tertile groups (HR 11.28, 95% CI 4.82-26.94; P < 0.001).

Conclusion: STEMI patients with high admission MIF level experienced a poorer recovery of cardiac function and worse long-term adverse outcomes. Combination of Nt-proBNP with MIF further improves prognostic capability.
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http://dx.doi.org/10.1093/ehjqcco/qcy020DOI Listing
July 2018
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