Publications by authors named "Ming-Hui Zou"

167 Publications

Assessment of postoperative risk factors for EEG abnormalities in routine clinical management after paediatric cardiopulmonary bypass.

Interact Cardiovasc Thorac Surg 2021 Apr 6. Epub 2021 Apr 6.

Heart Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong, China.

Objectives: The postoperative risk factors for electroencephalogram(EEG) abnormalities after paediatric cardiopulmonary bypass (CPB) remain to be identified. We investigated the characteristics of EEG abnormalities and risk factors in routine clinical management post-CPB.

Methods: EEG and cerebral oxygen saturation (ScO2) were monitored in 96 patients (aged 3 days, 37 months, median 5 months) for 72 h post-CPB. Clinical measurements included 4-hourly arterial and central venous pressure, arterial blood gases, doses of inotropic and vasoactive drugs, daily C-reactive protein (CRP) and NT-proB-type Natriuretic Peptide (NT-proBNP). Demographics, STAT categories and outcomes (duration of mechanical ventilation, CICU stay) were recorded. Un.

Results: Seizures occurred in 20 patients (20.8%) beginning at 0-48 hand lasting 10 min-31 h; background abnormalities occurred in 67 (69.8%) beginning at 0-8 h and lasting 4-48 h. Patients with EEG abnormalities had worse outcomes. In univariable regression, seizures positively correlated with STAT categories, CPB time, temperature, blood pressure, central venous pressure, NT-proBNP, CRP, lactate and epinephrine, negatively with ScO2 and PaCO2 (P < 0.001 for lactate and epinephrine, P < 0.1 for the remaining). The degree of background abnormalities positively correlated with STAT categories, CPB time, operative time, central venous pressure, milrinone, negatively with blood pressure (P = 0.0003-0.087); it negatively correlated with lower dose of epinephrine (P < 0.001) and positively with higher dose (P = 0.03l). In multivariable regression, seizures positively correlated with epinephrine, lactate and temperature; the background abnormality correlations remain significant except for milrinone and operative time (P < 0.001 for epinephrine, P < 0.05 for the remaining).

Conclusions: Numerous perioperative risk factors are associated with EEG abnormalities post-CPB. The most significant and consistent risk factor is epinephrine.
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http://dx.doi.org/10.1093/icvts/ivab081DOI Listing
April 2021

RETRACTION: Hypochlorous acid via peroxynitrite activates protein kinase Cθ and insulin resistance in adipocytes.

J Mol Endocrinol 2021 Feb;66(2):Z1

Section of Molecular Medicine, BSEB 306A, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

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http://dx.doi.org/10.1530/JME-14-0213rDOI Listing
February 2021

A High-Fat Diet Attenuates AMPK α1 in Adipocytes to Induce Exosome Shedding and Nonalcoholic Fatty Liver Development In Vivo.

Diabetes 2021 Feb 1;70(2):577-588. Epub 2020 Dec 1.

Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA.

Exosomes are important for intercellular communication, but the role of exosomes in the communication between adipose tissue (AT) and the liver remains unknown. The aim of this study is to determine the contribution of AT-derived exosomes in nonalcoholic fatty liver disease (NAFLD). Exosome components, liver fat content, and liver function were monitored in AT in mice fed a high-fat diet (HFD) or treated with metformin or GW4869 and with AMPKα1-floxed /wild-type [WT]), , liver tissue-specific , or AT-specific modification. In cultured adipocytes and white AT, the absence of increased exosome release and exosomal proteins by elevating tumor susceptibility gene 101 ()-mediated exosome biogenesis. In adipocytes treated with palmitic acid, TSG101 facilitated scavenger receptor class B (CD36) sorting into exosomes. CD36-containing exosomes were then endocytosed by hepatocytes to induce lipid accumulation and inflammation. Consistently, an HFD induced more severe lipid accumulation and cell death in and AT-specific mice than in WT and liver-specific mice. AMPK activation by metformin reduced adipocyte-mediated exosome release and mitigated fatty liver development in WT and liver-specific mice. Moreover, administration of the exosome inhibitor GW4869 blocked exosome secretion and alleviated HFD-induced fatty livers in and adipocyte-specific mice. We conclude that HFD-mediated AMPKα1 inhibition promotes NAFLD by increasing numbers of AT CD36-containing exosomes.
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http://dx.doi.org/10.2337/db20-0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881856PMC
February 2021

BRD4 inhibition by JQ1 prevents high-fat diet-induced diabetic cardiomyopathy by activating PINK1/Parkin-mediated mitophagy in vivo.

J Mol Cell Cardiol 2020 12 15;149:1-14. Epub 2020 Sep 15.

Department of Chemistry, Georgia State University, Atlanta, GA 30303, United States of America; Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA 30303, United States of America. Electronic address:

BRD4 is a member of the BET family of epigenetic regulators. Inhibition of BRD4 by the selective bromodomain inhibitor JQ1, alleviates thoracic aortic constriction-induced cardiac hypertrophy and heart failure. However, whether BRD4 inhibition by JQ1 has therapeutic effect on diabetic cardiomyopathy, a major cause of heart failure in patients with Type 2 diabetes, remains unknown. Here, we discover a novel link between BRD4 and PINK1/Parkin-mediated mitophagy during diabetic cardiomyopathy. Upregulation of BRD4 in diabetic mouse hearts inhibits PINK1/Parkin-mediated mitophagy, resulting in accumulation of damaged mitochondria and subsequent impairment of cardiac structure and function. BRD4 inhibition by JQ1 improves mitochondrial function, and repairs the cardiac structure and function of the diabetic heart. These effects depended on rewiring of the BRD4-driven transcription and repression of PINK1. Deletion of Pink1 suppresses mitophagy, exacerbates cardiomyopathy, and abrogates the therapeutic effect of JQ1 on diabetic cardiomyopathy. Our results illustrate a valid therapeutic strategy for treating diabetic cardiomyopathy by inhibition of BRD4.
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http://dx.doi.org/10.1016/j.yjmcc.2020.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736123PMC
December 2020

AMPK, Mitochondrial Function, and Cardiovascular Disease.

Int J Mol Sci 2020 Jul 15;21(14). Epub 2020 Jul 15.

Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA 30303, USA.

Adenosine monophosphate-activated protein kinase (AMPK) is in charge of numerous catabolic and anabolic signaling pathways to sustain appropriate intracellular adenosine triphosphate levels in response to energetic and/or cellular stress. In addition to its conventional roles as an intracellular energy switch or fuel gauge, emerging research has shown that AMPK is also a redox sensor and modulator, playing pivotal roles in maintaining cardiovascular processes and inhibiting disease progression. Pharmacological reagents, including statins, metformin, berberine, polyphenol, and resveratrol, all of which are widely used therapeutics for cardiovascular disorders, appear to deliver their protective/therapeutic effects partially via AMPK signaling modulation. The functions of AMPK during health and disease are far from clear. Accumulating studies have demonstrated crosstalk between AMPK and mitochondria, such as AMPK regulation of mitochondrial homeostasis and mitochondrial dysfunction causing abnormal AMPK activity. In this review, we begin with the description of AMPK structure and regulation, and then focus on the recent advances toward understanding how mitochondrial dysfunction controls AMPK and how AMPK, as a central mediator of the cellular response to energetic stress, maintains mitochondrial homeostasis. Finally, we systemically review how dysfunctional AMPK contributes to the initiation and progression of cardiovascular diseases via the impact on mitochondrial function.
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http://dx.doi.org/10.3390/ijms21144987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404275PMC
July 2020

Oxidative Stress, GTPCH1, and Endothelial Nitric Oxide Synthase Uncoupling in Hypertension.

Antioxid Redox Signal 2021 Mar 27;34(9):750-764. Epub 2020 May 27.

Center for Molecular and Translational Medicine, Georgia State University, Atlanta, Georgia, USA.

Hypertension has major health consequences, which is associated with endothelial dysfunction. Endothelial nitric oxide synthase (eNOS)-produced nitric oxide (NO) signaling in the vasculature plays an important role in maintaining vascular homeostasis. Considering the importance of NO system, this review aims to provide a brief overview of the biochemistry of members of NO signaling, including GTPCH1 [guanosine 5'-triphosphate (GTP) cyclohydrolase 1], tetrahydrobiopterin (BH), and eNOS. Being NO signaling activators and regulators of eNOS signaling, BH treatment is getting widespread attention either as potential therapeutic agents or as preventive agents. Recent clinical trials also support that BH treatment could be considered a promising therapeutic in hypertension. Under conditions of BH depletion, eNOS-generated superoxides trigger pathological events. Abnormalities in NO availability and BH deficiency lead to disturbed redox regulation causing pathological events. This disturbed signaling influences the development of systemic hypertension as well as pulmonary hypertension. Considering the importance of BH and NO to improve the translational significance, it is essential to continue research on this field to manipulate BH to increase the efficacy for treating hypertension. Thus, this review also examines the current state of knowledge on the effects of eNOS activators on preclinical models and humans to utilize this information for potential therapy.
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http://dx.doi.org/10.1089/ars.2020.8112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910417PMC
March 2021

Loss of AMPKalpha1 Triggers Centrosome Amplification via PLK4 Upregulation in Mouse Embryonic Fibroblasts.

Int J Mol Sci 2020 Apr 16;21(8). Epub 2020 Apr 16.

Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA 30302, USA.

Recent evidence indicates that activation of adenosine monophosphate-activated protein kinase (AMPK), a highly conserved sensor and modulator of cellular energy and redox, regulates cell mitosis. However, the underlying molecular mechanisms for AMPKα subunit regulation of chromosome segregation remain poorly understood. This study aimed to ascertain if AMPKα1 deletion contributes to chromosome missegregation by elevating Polo-like kinase 4 (PLK4) expression. Centrosome proteins and aneuploidy were monitored in cultured mouse embryonic fibroblasts (MEFs) isolated from wild type (WT, C57BL/6J) or AMPKα1 homozygous deficient (AMPKα1) mice by Western blotting and metaphase chromosome spread. Deletion of AMPKα1, the predominant AMPKα isoform in immortalized MEFs, led to centrosome amplification and chromosome missegregation, as well as the consequent aneuploidy (34-66%) and micronucleus. Furthermore, AMPKα1 null cells exhibited a significant induction of PLK4. Knockdown of nuclear factor kappa B2/p52 ameliorated the PLK4 elevation in AMPKα1-deleted MEFs. Finally, PLK4 inhibition by Centrinone reversed centrosome amplification of AMPKα1-deleted MEFs. Taken together, our results suggest that AMPKα1 plays a fundamental role in the maintenance of chromosomal integrity through the control of p52-mediated transcription of PLK4, a trigger of centriole biogenesis.
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http://dx.doi.org/10.3390/ijms21082772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216113PMC
April 2020

Targeting senescent cells to attenuate cardiovascular disease progression.

Ageing Res Rev 2020 07 13;60:101072. Epub 2020 Apr 13.

Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street SE, Atlanta, GA, 30303, United States.

Cardiovascular disease (CVD) is the most common disease to increase as life expectancy increases. Most high-profile pharmacological treatments for age-related CVD have led to inefficacious results, implying that novel approaches to treating these pathologies are needed. Emerging data have demonstrated that senescent cardiovascular cells, which are characterized by irreversible cell cycle arrest and a distinct senescence-associated secretory phenotype, accumulate in aged or diseased cardiovascular systems, suggesting that they may impair cardiovascular function. This review discusses the evidence implicating senescent cells in cardiovascular ageing, the onset and progression of CVD, and the molecular mechanisms underlying cardiovascular cell senescence. We also review eradication of senescent cardiovascular cells by small-molecule-drug-mediated apoptosis and immune cell-mediated efferocytosis and toxicity as promising and precisely targeted therapeutics for CVD prevention and treatment.
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http://dx.doi.org/10.1016/j.arr.2020.101072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263313PMC
July 2020

β-hydroxybutyrate and its metabolic effects on age-associated pathology.

Exp Mol Med 2020 04 8;52(4):548-555. Epub 2020 Apr 8.

Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA, USA.

Aging is a universal process that renders individuals vulnerable to many diseases. Although this process is irreversible, dietary modulation and caloric restriction are often considered to have antiaging effects. Dietary modulation can increase and maintain circulating ketone bodies, especially β-hydroxybutyrate (β-HB), which is one of the most abundant ketone bodies in human circulation. Increased β-HB has been reported to prevent or improve the symptoms of various age-associated diseases. Indeed, numerous studies have reported that a ketogenic diet or ketone ester administration alleviates symptoms of neurodegenerative diseases, cardiovascular diseases, and cancers. Considering the potential of β-HB and the intriguing data emerging from in vivo and in vitro experiments as well as clinical trials, this therapeutic area is worthy of attention. In this review, we highlight studies that focus on the identified targets of β-HB and the cellular signals regulated by β-HB with respect to alleviation of age-associated ailments.
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http://dx.doi.org/10.1038/s12276-020-0415-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210293PMC
April 2020

Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases.

Cells 2020 03 10;9(3). Epub 2020 Mar 10.

Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street SE, Atlanta, GA 30303, USA.

Senescent cells are generally characterized by permanent cell cycle arrest, metabolic alteration and activation, and apoptotic resistance in multiple organs due to various stressors. Excessive accumulation of senescent cells in numerous tissues leads to multiple chronic diseases, tissue dysfunction, age-related diseases and organ ageing. Immune cells can remove senescent cells. Immunaging or impaired innate and adaptive immune responses by senescent cells result in persistent accumulation of various senescent cells. Although senolytics-drugs that selectively remove senescent cells by inducing their apoptosis-are recent hot topics and are making significant research progress, senescence immunotherapies using immune cell-mediated clearance of senescent cells are emerging and promising strategies to fight ageing and multiple chronic diseases. This short review provides an overview of the research progress to date concerning senescent cell-caused chronic diseases and tissue ageing, as well as the regulation of senescence by small-molecule drugs in clinical trials and different roles and regulation of immune cells in the elimination of senescent cells. Mounting evidence indicates that immunotherapy targeting senescent cells combats ageing and chronic diseases and subsequently extends the healthy lifespan.
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http://dx.doi.org/10.3390/cells9030671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140645PMC
March 2020

Autophagic degradation of KAT2A/GCN5 promotes directional migration of vascular smooth muscle cells by reducing TUBA/α-tubulin acetylation.

Autophagy 2020 10 27;16(10):1753-1770. Epub 2019 Dec 27.

Center of Molecular and Translational Medicine, Georgia State University , Atlanta, GA, USA.

Macroautophagy/autophagy, a fundamental process for degradation of macromolecules and organelles, occurs constitutively at a basal level and is upregulated in response to stress. Whether autophagy regulates protein acetylation and microtubule stability in vascular smooth muscle cells (VSMCs) migration, however, remains unknown. Here, we demonstrate that the histone acetyltransferase KAT2A/GCN5 (lysine acetyltransferase 2) binds directly to the autophagosome protein MAP1LC3/LC3 (microtubule associated protein 1 light chain 3) via a conserved LC3-interacting region (LIR) domain. This interaction is required for KAT2A sequestration in autophagosomes and degradation by lysosomal acid hydrolases. Suppression of autophagy results in KAT2A accumulation. KAT2A functions as an acetyltransferase to increase TUBA/α-tubulin acetylation, promote microtubule polymerization and stability, ultimately inhibiting directional cell migration. Our findings indicate that deacetylation of TUBA and perturbation of microtubule stability via selective autophagic degradation of KAT2A are essential for autophagy-promoting VSMC migration. ACTB: actin beta; ATAT1: alpha tubulin acetyltransferase 1; ATG: autophagy-related; BECN1: beclin 1; CQ: chloroquine; FBS: fetal bovine serum; GST: glutathione S-transferase; H4K16ac: histone H4 lysine 16 acetylation; HASMCs: human aortic smooth muscle cells; HBSS: Hank's buffered salt solution; HDAC6: histone deacetylase 6; hMOF: human males absent on the first; IP: immunoprecipitation; KAT2A/GCN5: lysine acetyltransferase 2A; Lacta: lactacystin; LIR: LC3-interaction region; MAP1LC3: microtubule associated protein 1 light chain 3; MEFs: mouse embryonic fibroblasts; MTOC: microtubule-organizing center; PE: phosphatidylethanolamine; PtdIns3K: class III phosphatidylinositol 3-kinase; RUNX2: runt-related transcription factor 2; SIRT1: sirtuin 1; SIRT2: sirtuin 2; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like autophagy activating kinase 1; VSMCs: vascular smooth muscle cells; WT: wild-type.
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http://dx.doi.org/10.1080/15548627.2019.1707488DOI Listing
October 2020

Cardiomyocyte-Specific Prevents Inflammation in the Heart.

J Am Heart Assoc 2019 11 13;8(22):e012792. Epub 2019 Nov 13.

Division of Neonatology Department of Pediatrics Developmental Vascular Biology Program, Children's Research Institute Medical College of Wisconsin Milwaukee WI.

Background The SNRK (sucrose-nonfermenting-related kinase) enzyme is critical for cardiac function. However, the underlying cause for heart failure observed in cardiac conditional knockout mouse is unknown. Methods and Results Previously, 6-month adult mice knocked out for in cardiomyocytes (CMs) displayed left ventricular dysfunction. Here, 4-month adult mice, on angiotensin II (Ang II) infusion, show rapid decline in cardiac systolic function, which leads to heart failure and death in 2 weeks. These mice showed increased expression of nuclear factor κ light chain enhancer of activated B cells (NF-κB), inflammatory signaling proteins, proinflammatory proteins in the heart, and fibrosis. Interestingly, under Ang II infusion, mice knocked out for in endothelial cells did not show significant systolic or diastolic dysfunction. Although an NF-κB inflammation signaling pathway was increased in knockout endothelial cells, this did not lead to fibrosis or mortality. In hearts of adult mice knocked out for in CMs, we also observed NF-κB pathway activation in CMs, and an increased presence of Mac2 macrophages was observed in basal and Ang II-infused states. In vitro analysis of knockdown HL-1 CMs revealed similar upregulation of the NF-κB signaling proteins and proinflammatory proteins that was exacerbated on Ang II treatment. The Ang II-induced NF-κB pathway-mediated proinflammatory effects were mediated in part through protein kinase B or AKT, wherein AKT inhibition restored the proinflammatory signaling protein levels to baseline in knockdown HL-1 CMs. Conclusions During heart failure, SNRK acts as a cardiomyocyte-specific repressor of cardiac inflammation and fibrosis.
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http://dx.doi.org/10.1161/JAHA.119.012792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915262PMC
November 2019

Propranolol exhibits activity against hemangiomas independent of beta blockade.

NPJ Precis Oncol 2019 1;3:27. Epub 2019 Nov 1.

1Department of Dermatology, Emory University School of Medicine, Atlanta, GA 30322 USA.

Propranolol is a widely used beta blocker that consists of a racemic mixture of R and S stereoisomers. Only the S stereoisomer has significant activity against the beta-adrenergic receptor. A fortuitous clinical observation was made in an infant who received propranolol for cardiac disease, and regression of a hemangioma of infancy was noted. This has led to the widespread use of propranolol for the treatment of large and life-threatening hemangiomas of infancy. Infants receiving propranolol require monitoring to ensure that they do not suffer from side effects related to beta blockade. The exact mechanism of activity of propranolol in hemangioma of infancy is unknown. In this study, we treated hemangioma stem cells with both beta blockade active S- and inactive R-propranolol and looked for genes that were coordinately regulated by this treatment. Among the genes commonly downregulated, Angiopoietin-like 4 (ANGPTL4) was among the most regulated. We confirmed that propranolol isomers downregulated ANGPTL4 in endothelial cells, with greater downregulation of ANGPTL4 using the beta blockade inactive R-propranolol. ANGPTL4 is present in human hemangiomas of infancy. Finally, R-propranolol inhibited the growth of bEnd.3 hemangioma cells in vivo. The implication of this is that hemangioma growth can be blocked without the side effects of beta blockade. Given that humans have been exposed to racemic propranolol for decades and thus to R-propranolol, clinical development of R-propranolol for hemangiomas of infancy and other angiogenic diseases is warranted.
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http://dx.doi.org/10.1038/s41698-019-0099-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825155PMC
November 2019

Publisher Correction: Circulating miR-103a-3p contributes to angiotensin II-induced renal inflammation and fibrosis via a SNRK/NF-κB/p65 regulatory axis.

Nat Commun 2019 Aug 6;10(1):3628. Epub 2019 Aug 6.

Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-019-11515-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684531PMC
August 2019

Peroxynitrite-Mediated SIRT (Sirtuin)-1 Inactivation Contributes to Nicotine-Induced Arterial Stiffness in Mice.

Arterioscler Thromb Vasc Biol 2019 07 16;39(7):1419-1431. Epub 2019 May 16.

From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta.

Objective- Inhibition of SIRT (sirtuin)-1, a nicotinamide adenine dinucleotide-dependent protein deacetylase, is linked to cigarette smoking-induced arterial stiffness, but the underlying mechanisms remain largely unknown. The aim of the present study was to determine the effects and mechanisms of nicotine, a major component of cigarette smoke, on SIRT1 activity and arterial stiffness. Approach and Results- Arterial stiffness, peroxynitrite (ONOO) formation, SIRT1 expression and activity were monitored in mouse aortas of 8-week-old C57BL/6 mice (wild-type) or Sirt1-overexpressing ( Sirt1 ) mice with or without nicotine for 4 weeks. In aortas of wild-type mice, nicotine reduced SIRT1 protein and activity by ≈50% without affecting its mRNA levels. In those from Sirt1 mice, nicotine also markedly reduced SIRT1 protein and activity to the levels that were comparable to those in wild-type mice. Nicotine infusion significantly induced collagen I, fibronectin, and arterial stiffness in wild-type but not Sirt1 mice. Nicotine increased the levels of iNOS (inducible nitric oxide synthase) and the co-staining of SIRT1 and 3-nitrotyrosine, a footprint of ONOO in aortas. Tempol, which ablated ONOO by scavenging superoxide anion, reduced the effects of nicotine on SIRT1 and collagen. Mutation of zinc-binding cysteine 395 or 398 in SIRT1 into serine (C395S) or (C398S) abolished SIRT1 activity. Furthermore, ONOO dose-dependently inhibited the enzyme and increased zinc release in recombinant SIRT1. Finally, we found SIRT1 inactivation by ONOO activated the YAP (Yes-associated protein) resulting in abnormal ECM (extracellular matrix) remodeling. Conclusions- Nicotine induces ONOO, which selectively inhibits SIRT1 resulting in a YAP-mediated ECM remodeling. Visual Overview- An online visual overview is available for this article.
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http://dx.doi.org/10.1161/ATVBAHA.118.312346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613385PMC
July 2019

Circulating miR-103a-3p contributes to angiotensin II-induced renal inflammation and fibrosis via a SNRK/NF-κB/p65 regulatory axis.

Nat Commun 2019 05 13;10(1):2145. Epub 2019 May 13.

Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA, USA.

Although angiotensin II (AngII) is known to cause renal injury and fibrosis, the underlying mechanisms remain poorly characterized. Here we show that hypertensive nephropathy (HN) patients and AngII-infused mice exhibit elevated levels of circulating miR103a-3p. We observe a positive correlation between miR-103a-3p levels and AngII-induced renal dysfunction. miR-103a-3p suppresses expression of the sucrose non-fermentable-related serine/threonine-protein kinase SNRK in glomerular endothelial cells, and glomeruli of HN patients and AngII-infused mice show reduced endothelial expression of SNRK. We find that SNRK exerts anti-inflammatory effects by interacting with activated nuclear factor-κB (NF-κB)/p65. Overall, we demonstrate that AngII increases circulating miR-103a-3p levels, which reduces SNRK levels in glomerular endothelial cells, resulting in the over-activation of NF-κB/p65 and, consequently, renal inflammation and fibrosis. Together, our work identifies miR-103a-3p/SNRK/NF-κB/p65 as a regulatory axis of AngII-induced renal inflammation and fibrosis.
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http://dx.doi.org/10.1038/s41467-019-10116-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513984PMC
May 2019

Hyperglycemia-Driven Inhibition of AMP-Activated Protein Kinase α2 Induces Diabetic Cardiomyopathy by Promoting Mitochondria-Associated Endoplasmic Reticulum Membranes In Vivo.

Circulation 2019 04;139(16):1913-1936

Center for Molecular and Translational Medicine, Georgia State University, Atlanta (S.W., Q.L., Y.D., Y.W., Y.Q., Z.X., M.-H.Z.).

Background: Fundc1 (FUN14 domain containing 1), an outer mitochondrial membrane protein, is important for mitophagy and mitochondria-associated endoplasmic reticulum membranes (MAMs). The roles of Fundc1 and MAMs in diabetic hearts remain unknown. The aims of this study, therefore, were to determine whether the diabetes mellitus-induced Fundc1 expression could increase MAM formation, and whether disruption of MAM formation improves diabetic cardiac function.

Methods: Levels of FUNDC1 were examined in the hearts from diabetic patients and nondiabetic donors. Levels of Fundc1-induced MAMs and mitochondrial and heart function were examined in mouse neonatal cardiomyocytes exposed to high glucose (HG, 30 mmol/L d-glucose for 48 hours), and in streptozotocin-treated cardiac-specific Fundc1 knockout mice and cardiac-specific Fundc1 knockout diabetic Akita mice, as well.

Results: FUNDC1 levels were significantly elevated in cardiac tissues from diabetic patients in comparison with those from nondiabetic donors. In cultured mouse neonatal cardiomyocytes, HG conditions increased levels of Fundc1, the inositol 1,4,5-trisphosphate type 2 receptor (Ipr2), and MAMs. Genetic downregulation of either Fundc1 or Ipr2 inhibited MAM formation, reduced endoplasmic reticulum-mitochondrial Ca flux, and improved mitochondrial function in HG-treated cardiomyocytes. Consistently, adenoviral overexpression of Fundc1 promoted MAM formation, mitochondrial Ca increase, and mitochondrial dysfunction in cardiomyocytes exposed to normal glucose (5.5 mmol/L d-glucose). In comparison with nondiabetic controls, levels of Fundc1, Ipr2, and MAMs were significantly increased in hearts from streptozotocin-treated mice and Akita mice. Furthermore, in comparison with control hearts, diabetes mellitus markedly increased coimmunoprecipitation of Fundc1 and Ipr2. The binding of Fundc1 to Ipr2 inhibits Ipr2 ubiquitination and proteasome-mediated degradation. Cardiomyocyte-specific Fundc1 deletion ablated diabetes mellitus-induced MAM formation, prevented mitochondrial Ca increase, mitochondrial fragmentation, and apoptosis with improved mitochondrial functional capacity and cardiac function. In mouse neonatal cardiomyocytes, HG suppressed AMP-activated protein kinase activity. Furthermore, in cardiomyocytes of Prkaa2 knockout mice, expression of Fundc1, MAM formation, and mitochondrial Ca levels were significantly increased. Finally, adenoviral overexpression of a constitutively active mutant AMP-activated protein kinase ablated HG-induced MAM formation and mitochondrial dysfunction.

Conclusions: We conclude that diabetes mellitus suppresses AMP-activated protein kinase, initiating Fundc1-mediated MAM formation, mitochondrial dysfunction, and cardiomyopathy, suggesting that AMP-activated protein kinase-induced Fundc1 suppression is a valid target to treat diabetic cardiomyopathy.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.033552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465113PMC
April 2019