Publications by authors named "Zhaohui Pei"

18 Publications

  • Page 1 of 1

FUNDC1 insufficiency sensitizes high fat diet intake-induced cardiac remodeling and contractile anomaly through ACSL4-mediated ferroptosis.

Metabolism 2021 Sep 29;122:154840. Epub 2021 Jul 29.

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA. Electronic address:

Objective: Ferroptosis is indicated in cardiovascular diseases. Given the prominent role of mitophagy in the governance of ferroptosis and our recent finding for FUN14 domain containing 1 (FUNDC1) in obesity anomalies, this study evaluated the impact of FUNDC1 deficiency in high fat diet (HFD)-induced cardiac anomalies.

Methods And Materials: WT and FUNDC1 mice were fed HFD (45% calorie from fat) or low fat diet (LFD, 10% calorie from fat) for 10 weeks in the presence of the ferroptosis inhibitor liproxstatin-1 (LIP-1, 10 mg/kg, i.p.).

Results: RNAseq analysis for differentially expressed genes (DEGs) reported gene ontology term related to ferroptosis and mitophagy in obese rat hearts, which was validated in obese rodent and human hearts. Although 10-week HFD intake did not alter global metabolism, cardiac geometry and function, ablation of FUNDC1 unmasked metabolic derangement, pronounced cardiac remodeling, contractile, intracellular Ca and mitochondrial anomalies upon HFD challenge, the effects of which with exception of global metabolism were attenuated or mitigated by LIP-1. FUNDC1 ablation unmasked HFD-evoked rises in fatty acid synthase ACSL4, necroptosis, inflammation, ferroptosis, mitochondrial O production, and mitochondrial injury as well as dampened autophagy and DNA repair enzyme 8-oxoG DNA glycosylase 1 (OGG1) but not apoptosis, the effect of which except ACSL4 and its regulator SP1 was reversed by LIP-1. In vitro data noted that arachidonic acid, an ACSL4 substrate, provoked cytochrome C release, cardiomyocyte defect, and lipid peroxidation under FUNDC1 deficiency, the effects were interrupted by inhibitors of SP1, ACSL4 and ferroptosis.

Conclusions: These data suggest that FUNDC1 deficiency sensitized cardiac remodeling and dysfunction with short-term HFD exposure, likely through ACSL4-mediated regulation of ferroptosis.
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http://dx.doi.org/10.1016/j.metabol.2021.154840DOI Listing
September 2021

Effect of Different Polymer Modifiers on the Long-Term Rutting and Cracking Resistance of Asphalt Mixtures.

Materials (Basel) 2021 Jun 17;14(12). Epub 2021 Jun 17.

College of Civil Science and Engineering, Yangzhou University, Yangzhou 225127, China.

To evaluate the long-term performances of different polymer-modified asphalt mixtures, three modifiers were chosen to modify AC-13 (defined as the asphalt concrete with the aggregate nominal maximum particle size of 13.2 mm); namely, high viscosity modifier (HVM), high modulus modifier (HMM), and anti-rutting agent (ARA). The deformation and cracking resistance of different polymer-modified mixtures were checked at different aging conditions (unaged, short-term aged, and long-term aged for 5, 10, and 15 days respectively). The results of the Hamburg wheel-track test and uniaxial penetration test (UPT) showed that the rutting resistance of all asphalt mixtures changed in a V-shape as the aging progressed. From the unaged stage to the long-term aging stage (5 days), the rutting resistance decreases gradually. While after the long-term aging stage (5 days), the rutting resistance increases gradually. Results from the semicircular bending test (SCB) and the indirect tensile asphalt cracking test (IDEAL-CT) indicated that the cracking resistance of all the mixtures gradually decline with the deepening of the aging degree, indicating that aging weakens the crack resistance of asphalt mixtures. Additionally, test results showed that the rutting resistance of ARA AC-13 (defined as AC-13 containing ARA) is the best, the cracking resistances of ARA AC-13, HMM AC-13 (defined as AC-13 containing HMM) and HVM AC-13 (defined as AC-13 containing HVM) have no significant difference, and different polymer modifiers had different sensitivities to aging due to the polymer content and the type of modifier. The conclusions of this study help to further understand the long-term performance of polymer-modified asphalt mixtures during service life and to help guide the selection of modifiers for mixtures.
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http://dx.doi.org/10.3390/ma14123359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234064PMC
June 2021

Beclin1 Haploinsufficiency accentuates second-hand smoke exposure -induced myocardial Remodeling and contractile dysfunction through a STING-mediated mechanism.

J Mol Cell Cardiol 2020 11 3;148:78-88. Epub 2020 Sep 3.

University of Wyoming College of Health Sciences, Laramie, WY 82071, USA; Department of Cardiology, Shanghai Institutes of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China. Electronic address:

Second-hand smoking evokes inflammation and cardiovascular diseases. Recent evidence has revealed a pivotal role for deranged autophagy in smoke exposure-induced cardiac anomalies. This study evaluated the impact of haploinsufficiency of the mTOR-independent autophagy protein Beclin1 on side-stream smoke exposure-induced cardiac anomalies and mechanism(s) involved. Adult WT and Beclin1 haploinsufficiency (Becn) mice were exposed to cigarette smoke for 1 h daily for 90 days. Echocardiographic, cardiomyocyte function, intracellular Ca, autophagy, mitophagy, apoptosis and inflammation were examined. DHE staining was employed to evaluate O level. Our data revealed that Beclin1 deficiency exacerbated smoke exposure-induced myocardial anomalies in geometry, fractional shortening, cardiomyocyte function, intracellular Ca handling, TEM ultrastructure, and inflammation along with pronounced apoptosis and O production. Side-stream smoke provoked excessive autophagy/mitophagy, mtDNA release, and activation of innate immune response signals cyclic GMP-AMP synthase (cGAS) and its effector - stimulator of interferon genes (STING), the effect was abolished or unaffected by Becn haploinsufficiency. STING phosphorylation was overtly promoted by smoke exposure in Becn mice. Smoke exposure also suppressed phosphorylation of mTOR although it facilitated that of ULK1 in both groups. In vitro data revealed that inhibition of cGAS or STING failed to affect smoke extract-induced mitophagy although they abrogated smoke extract-induced cardiomyocyte dysfunction except cGAS inhibition in Becn mice. These data suggest that Beclin1 is integral in the maintenance of cardiac homeostasis under side-stream smoke exposure via a STING-mediated mechanism.
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http://dx.doi.org/10.1016/j.yjmcc.2020.08.016DOI Listing
November 2020

Double knockout of Akt2 and AMPK accentuates high fat diet-induced cardiac anomalies through a cGAS-STING-mediated mechanism.

Biochim Biophys Acta Mol Basis Dis 2020 10 5;1866(10):165855. Epub 2020 Jun 5.

Department of Cardiology, Fudan University Zhongshan Hospital, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Fudan University Zhongshan Hospital, Shanghai 200032, China. Electronic address:

High fat diet intake contributes to undesired cardiac geometric and functional changes although the underlying mechanism remains elusive. Akt and AMPK govern to cardiac homeostasis. This study examined the impact of deletion of Akt2 (main cardiac isoform of Akt) and AMPKα2 on high fat diet intake-induced cardiac remodeling and contractile anomalies and mechanisms involved. Cardiac geometry, contractile, and intracellular Ca properties were evaluated using echocardiography, IonOptix® edge-detection and fura-2 techniques in wild-type (WT) and Akt2-AMPK double knockout (DKO) mice receiving low fat (LF) or high fat (HF) diet for 4 months. Our results revealed that fat diet intake elicit obesity, cardiac remodeling (hypertrophy, LV mass, LVESD, and cross-sectional area), contractile dysfunction (fractional shortening, peak shortening, maximal velocity of shortening/relengthening, time-to-90% relengthening, and intracellular Ca handling), ultrastructural disarray, apoptosis, O, inflammation, dampened autophagy and mitophagy. Although DKO did not affect these parameters, it accentuated high fat diet-induced cardiac remodeling and contractile anomalies. High fat intake upregulated levels of cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and STING phosphorylation while suppressing phosphorylation of ULK1 (Ser and Ser), with a more pronounced effect in DKO mice. In vitro data revealed that inhibition of cGAS and STING using PF-06928215 and Astin C negated palmitic acid-induced cardiomyocyte contractile dysfunction. Biological function analysis for all differentially expressed genes (DEGs) depicted that gene ontology terms associated with Akt and AMPK signaling processes were notably changed in high fat-fed hearts. Our data indicate that Akt2-AMPK ablation accentuated high fat diet-induced cardiac anomalies possibly through a cGAS-STING-mechanism.
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http://dx.doi.org/10.1016/j.bbadis.2020.165855DOI Listing
October 2020

CD74 knockout protects against LPS-induced myocardial contractile dysfunction through AMPK-Skp2-SUV39H1-mediated demethylation of BCLB.

Br J Pharmacol 2020 04 11;177(8):1881-1897. Epub 2020 Feb 11.

Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Fudan University Zhongshan Hospital, Shanghai, China.

Background And Purpose: Lipopolysaccharides (LPS), an outer membrane component of Gram-negative bacteria, triggers myocardial anomalies in sepsis. Recent findings indicated a role for inflammatory cytokine MIF and its receptor, CD74, in septic organ injury, although little is known of the role of MIF-CD74 in septic cardiomyopathy.

Experimental Approach: This study evaluated the impact of CD74 ablation on endotoxaemia-induced cardiac anomalies. Echocardiographic, cardiomyocyte contractile and intracellular Ca properties were examined.

Key Results: Our data revealed compromised cardiac function (lower fractional shortening, enlarged LV end systolic diameter, decreased peak shortening, maximal velocity of shortening/relengthening, prolonged duration of relengthening and intracellular Ca mishandling) and ultrastructural derangement associated with inflammation, O production, apoptosis, excess autophagy, phosphorylation of AMPK and JNK and dampened mTOR phosphorylation. These effects were attenuated or mitigated by CD74 knockout. LPS challenge also down-regulated Skp2, an F-box component of Skp1/Cullin/F-box protein-type ubiquitin ligase, while up-regulating that of SUV39H1 and H3K9 methylation of the Bcl2 protein BCLB. These effects were reversed by CD74 ablation. In vitro study revealed that LPS facilitated GFP-LC3B formation and cardiomyocyte defects. These effects were prevented by CD74 ablation. Interestingly, the AMPK activator AICAR, the autophagy inducer rapamycin and the demethylation inhibitor difenoconazole inhibited the effects of CD74 ablation against LPS-induced cardiac dysfunction, while the SUV39H1 inhibitor chaetocin or methylation inhibitor 5-AzaC ameliorated LPS-induced GFP-LC3B formation and cardiomyocyte contractile dysfunction.

Conclusion And Implications: Our data suggested that CD74 ablation protected against LPS-induced cardiac anomalies, O production, inflammation and apoptosis through suppression of autophagy in a Skp2-SUV39H1-mediated mechanism.
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http://dx.doi.org/10.1111/bph.14959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070165PMC
April 2020

Inhibition of CYP2E1 attenuates myocardial dysfunction in a murine model of insulin resistance through NLRP3-mediated regulation of mitophagy.

Biochim Biophys Acta Mol Basis Dis 2019 01 16;1865(1):206-217. Epub 2018 Aug 16.

Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai 210032, China; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA. Electronic address:

Insulin resistance leads to myocardial contractile dysfunction and deranged autophagy although the underlying mechanism or targeted therapeutic strategy is still lacking. This study was designed to examine the impact of inhibition of the cytochrome P450 2E1 (CYP2E1) enzyme on myocardial function and mitochondrial autophagy (mitophagy) in an Akt2 knockout model of insulin resistance. Adult wild-type (WT) and Akt2 mice were treated with the CYP2E1 inhibitor diallyl sulfide (100 mg/kg/d, i.p.) for 4 weeks. Cardiac geometry and function were assessed using echocardiographic and IonOptix systems. Western blot analysis was used to evaluate autophagy, mitophagy, inducible NOS (iNOS), and the NLRP3 inflammasome, a multi-protein intracellular pattern recognition receptor complex. Akt2 deletion triggered insulin resistance, compromised cardiac contractile and intracellular Ca property, mitochondrial ultrastructural damage, elevated O2 production, as well as suppressed autophagy and mitophagy, accompanied with elevated levels of NLRP3 and iNOS, the effects of which were significantly attenuated or ablated by diallyl sulfide. In vitro studies revealed that the NLRP3 activator nigericin nullified diallyl sulfide-offered benefit against Akt2 knockout on cardiomyocyte mechanical function and mitophagy (using Western blot and colocalization of GFP-LC3 and MitoTracker Red). Moreover, inhibition of iNOS but not mitochondrial ROS production attenuated Akt2 deletion-induced activation of NLRP3, substantiating a role for iNOS-mediated NLRP3 in insulin resistance-induced changes in mitophagy and cardiac dysfunction. In conclusion, these data depict that insulin resistance through CYP2E1 may contribute to the pathogenesis of myopathic changes including myocardial contractile dysfunction, oxidative stress and mitochondrial injury, possibly through activation of iNOS and NLRP3 signaling.
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http://dx.doi.org/10.1016/j.bbadis.2018.08.017DOI Listing
January 2019

Role of autophagy in inherited metabolic and endocrine myopathies.

Biochim Biophys Acta Mol Basis Dis 2019 01 18;1865(1):48-55. Epub 2018 Oct 18.

Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA. Electronic address:

The prevalence of cardiometabolic disease has reached an exponential rate of rise over the last decades owing to high fat/high caloric diet intake and satiety life style. Although the presence of dyslipidemia, insulin resistance, hypertension and obesity mainly contributes to the increased incidence of cardiometabolic diseases, population-based, clinical and genetic studies have revealed a rather important role for inherited myopathies and endocrine disorders in the ever-rising metabolic anomalies. Inherited metabolic and endocrine diseases such as glycogen storage and lysosomal disorders have greatly contributed to the overall prevalence of cardiometabolic diseases. Recent evidence has demonstrated an essential role for proteotoxicity due to autophagy failure and/or dysregulation in the onset of inherited metabolic and endocrine disorders. Given the key role for autophagy in the degradation and removal of long-lived or injured proteins and organelles for the maintenance of cellular and organismal homeostasis, this mini-review will discuss the potential contribution of autophagy dysregulation in the pathogenesis of inherited myopathies and endocrine disorders, which greatly contribute to an overall rise in prevalence of cardiometabolic disorders. Molecular, clinical, and epidemiological aspects will be covered as well as the potential link between autophagy and metabolic anomalies thus target therapy may be engaged for these comorbidities.
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http://dx.doi.org/10.1016/j.bbadis.2018.10.023DOI Listing
January 2019

Cardiomyocyte-specific knockout of endothelin receptor a attenuates obesity cardiomyopathy.

Biochim Biophys Acta Mol Basis Dis 2018 10 18;1864(10):3339-3352. Epub 2018 Jul 18.

Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA. Electronic address:

Endothelin (ET)-1 is implicated in the pathophysiology of cardiovascular diseases although its role in obesity anomalies has not been fully elucidated. This study was designed to examine the impact of ET-1 receptor A (ET) ablation on obesity-induced changes in cardiac geometry and contractile function, as well as the mechanisms involved with a focus on autophagy. Cardiomyocyte-specific ET receptor knockout (ETAKO) and WT mice were fed either low-fat (10% calorie from fat) or high-fat (45% calorie from fat) diet for 24 weeks. Glucose tolerance test was examined to confirm insulin resistance. High-fat diet intake compromised myocardial geometry (enlarged left ventricular diameters in systole and diastole), morphology (cardiac hypertrophy, increased wall thickness and interstitial fibrosis), contractile function (reduced fractional shortening, ejection fraction and cardiomyocyte shortening) and intracellular Ca handling, the effect of which was significantly attenuated by ETAKO. TUNEL staining revealed overt apoptosis in high-fat-fed group, the effect was reverted by ETAKO. Western blot analysis noted that high-fat intake downregulated leptin receptor and PPARγ, insulin signaling (elevated basal/dampened insulin-stimulated phosphorylation of Akt and IRS1), phosphorylation of AMPK, ACC, upregulated GATA-4, ANP, NFATc3, PPARα, m-TOR/p70s6k signaling, which were attenuated by ETAKO with the exception of AMPK/ACC. Furthermore, high-fat intake suppressed cardiac autophagy, which was abrogated by ETAKO. In cultured murine cardiomyocytes, palmitic acid challenged mimicked high-fat diet-induced hypertrophic and autophagic responses, the effect of which were abolished by the ET receptor antagonist BQ123 or mTOR inhibitor rapamycin. These results suggest that inhibition of ET rescues high-fat intake-induced cardiac anomalies possibly through autophagy regulation.
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http://dx.doi.org/10.1016/j.bbadis.2018.07.020DOI Listing
October 2018

Inhibition of advanced glycation endproduct (AGE) rescues against streptozotocin-induced diabetic cardiomyopathy: Role of autophagy and ER stress.

Toxicol Lett 2018 Mar 22;284:10-20. Epub 2017 Nov 22.

Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA; Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai 210032, China. Electronic address:

Diabetes mellitus leads to oxidative stress and contractile dysfunction in the heart. Although several rationales have been speculated, the precise mechanism behind diabetic cardiomyopathy remains elusive. This study was designed to assess the role of inhibition of advanced glycation endproducts (AGE) in streptozotocin (STZ)-induced diabetic cardiac dysfunction. Cardiac contractile function was assessed in normal C57BL/6 and STZ (200mg/kg, single injection and maintained for 2 wks)-induced diabetic mice treated with or without the AGE inhibitor aminoguanidine (50mg/kg/d in drinking water) for 2 weeks using echocardiography and IonOptix MyoCam techniques. Diabetes compromised cardiac contractile function shown as reduced fractional shortening and ejection fraction, enlarged left ventricular end systolic/diastolic diameters, decreased peak shortening, maximal velocity of shortening/relengthening, prolonged shortening and relengthening duration as well as impaired intracellular Ca homeostasis, the effects of which were alleviated or reversed by aminoguanidine treatment. Diabetes also inhibited autophagy, increased ER stress and phosphorylation of pro-hypertrophic signaling molecules Akt and mTOR, the effect of which was reversed by aminoguanidine. In vitro study revealed that methylglyoxal-derived AGE (MG-AGE) incubation in isolated cardiomyocytes promoted oxidation of sarco(endo)plasmic reticulum Ca-ATPase (SERCA2a) and production of superoxide, the effects of which were negated by the autophagy inducer rapamycin, the ER stress chaperone TUDCA or the antioxidant N-acetylcysteine. Taken together, these data revealed that inhibition of AGE formation rescues against experimental diabetes-induced cardiac remodeling and contractile dysfunction possible through regulation of autophagy and ER stress.
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http://dx.doi.org/10.1016/j.toxlet.2017.11.018DOI Listing
March 2018

Ablation of Akt2 protects against lipopolysaccharide-induced cardiac dysfunction: role of Akt ubiquitination E3 ligase TRAF6.

J Mol Cell Cardiol 2014 Sep 5;74:76-87. Epub 2014 May 5.

Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA. Electronic address:

Lipopolysaccharide (LPS), an essential component of the outer membrane of Gram-negative bacteria, plays a pivotal role in myocardial anomalies in sepsis. Recent evidence has depicted a role of Akt in LPS-induced cardiac sequelae although little information is available with regard to the contribution of Akt isoforms in the endotoxin-induced cardiac dysfunction. This study examined the effect of Akt2 knockout on LPS-induced myocardial contractile dysfunction and the underlying mechanism(s) with a focus on TNF receptor-associated factor 6 (TRAF6). Echocardiographic properties and cardiomyocyte contractile function [peak shortening (PS), maximal velocity of shortening/relengthening, time-to-PS, time-to-90% relengthening] were examined in wild-type and Akt2 knockout mice following LPS challenge (4mg/kg, 4h). LPS challenge enlarged LV end systolic diameter, reduced fractional shortening and cardiomyocyte contractile capacity, prolonged TR90, promoted apoptosis, upregulated caspase-3/-12, ubiquitin, and the ubiquitination E3 ligase TRAF6 as well as decreased mitochondrial membrane potential without affecting the levels of TNF-α, toll-like receptor 4 and the mitochondrial protein ALDH2. Although Akt2 knockout failed to affect myocardial function, apoptosis, and ubiquitination, it significantly attenuated or mitigated LPS-induced changes in cardiac contractile and mitochondrial function, apoptosis and ubiquitination but not TRAF6. LPS facilitated ubiquitination, phosphorylation of Akt, GSK3β and p38, the effect of which with the exception of p38 was ablated by Akt2 knockout. TRAF6 inhibitory peptide or RNA silencing significantly attenuated LPS-induced Akt2 ubiquitination, cardiac contractile anomalies and apoptosis. These data collectively suggested that TRAF6 may play a pivotal role in mediating LPS-induced cardiac injury via Akt2 ubiquitination.
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http://dx.doi.org/10.1016/j.yjmcc.2014.04.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115010PMC
September 2014

α,β-Unsaturated aldehyde crotonaldehyde triggers cardiomyocyte contractile dysfunction: role of TRPV1 and mitochondrial function.

Pharmacol Res 2014 Apr 3;82:40-50. Epub 2014 Apr 3.

University of Wyoming College of Health Sciences, Laramie, WY 82071, USA. Electronic address:

Recent evidence has suggested that cigarette smoking is associated with an increased prevalence of heart diseases. Given that cigarette smoking triggers proinflammatory response via stimulation of the capsaicin-sensitive transient receptor potential cation channel TRPV1, this study was designed to evaluate the effect of an essential α,β-unsaturated aldehyde from cigarette smoke crotonaldehyde on myocardial function and the underlying mechanism with a focus on TRPV1 and mitochondria. Cardiomyocyte mechanical and intracellular Ca2+ properties were evaluated including peak shortening (PS), maximal velocity of shortening/relengthening (±dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR90), fura-2 fluorescence intensity (FFI), intracellular Ca2+ decay and SERCA activity. Apoptosis and TRPV1 were evaluated using Western blot analysis. Production of reactive oxygen species (ROS) and DNA damage were measured using the intracellular fluoroprobe 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate and 8-hydroxy-2'-deoxyguanosine (8-OHdG), respectively. Our data revealed that crotonaldehyde interrupted cardiomyocyte contractile and intracellular Ca2+ property including depressed PS, ±dL/dt, ΔFFI and SERCA activity, as well as prolonged TR90 and intracellular Ca2+ decay. Crotonaldehyde exposure increased TRPV1 and NADPH oxidase levels, promoted apoptosis, mitochondrial injury (decreased aconitase activity, PGC-1α and UCP-2) as well as production of ROS and 8-OHdG. Interestingly, crotonaldehyde-induced cardiac defect was obliterated by the ROS scavenger glutathione and the TRPV1 inhibitor capsazepine. Capsazepine (not glutathione) ablated crotonaldehyde-induced mitochondrial damage. Capsazepine, glutathione and the NADPH inhibitor apocynin negated crotonaldehyde-induced ROS accumulation. Our data suggest a role of crotonaldehyde compromises cardiomyocyte mechanical function possibly through a TRPV1- and mitochondria-dependent oxidative stress mechanism.
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http://dx.doi.org/10.1016/j.phrs.2014.03.010DOI Listing
April 2014

Cardiac peroxisome proliferator-activated receptor-γ expression is modulated by oxidative stress in acutely infrasound-exposed cardiomyocytes.

Cardiovasc Toxicol 2013 Dec;13(4):307-15

Department of Cardiology, The Third Hospital of Nanchang, Nanchang, 330009, Jiangxi, China,

The aim of the present study was to examine the effects of acute infrasound exposure on oxidative damage and investigate the underlying mechanisms in rat cardiomyocytes. Neonatal rat cardiomyocytes were cultured and exposed to infrasound for several days. In the study, the expression of CAT, GPx, SOD1, and SOD2 and their activities in rat cardiomyocytes in infrasound exposure groups were significantly decreased compared to those in the various time controls, along with significantly higher levels of O2 (-) and H2O2. Decreased cardiac cell viability was not observed in various time controls. A significant reduction in cardiac cell viability was observed in the infrasound group compared to the control, while significantly increased cardiac cell viability was observed in the infrasound exposure and rosiglitazone pretreatment group. Compared to the control, rosiglitazone significantly upregulated CAT, GPx, SOD1, and SOD2 expression and their activities in rat cardiomyocytes exposed to infrasound, while the levels of O2 (-) or H2O2 were significantly decreased. A potential link between a significant downregulation of PPAR-γ expression in rat cardiomyocytes in the infrasound group was compared to the control and infrasound-induced oxidative stress. These findings indicate that infrasound can induce oxidative damage in rat cardiomyocytes by inactivating PPAR-γ.
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http://dx.doi.org/10.1007/s12012-013-9211-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834180PMC
December 2013

AMPK activation enhances PPARα activity to inhibit cardiac hypertrophy via ERK1/2 MAPK signaling pathway.

Arch Biochem Biophys 2011 Jul 21;511(1-2):1-7. Epub 2011 Apr 21.

Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, PR China.

Activation of adenosine monophosphate-activated protein kinase (AMPK) has been shown to inhibit cardiac hypertrophy through peroxisome proliferators-activated receptor-α (PPARα) signaling pathway, but the detailed mechanism remains unclear. A rat model of cardiac hypertrophy created by transaortic constriction (TAC) was used to investigate the mechanism involved in regulation of PPARα activity by AMPK. It was observed that treatment with AICAR (5-aminoimidazole 1 carboxamide ribonucleoside), an AMPK activator, significantly inhibited cardiac hypertrophy in vivo and in vitro. Phosphorylated extracellular signal regulated protein kinase (phospho-ERK1/2) and phospho-p38 mitogen-activated protein kinase (MAPK) protein levels were significantly up-regulated, while PPARα protein level was down-regulated in TAC rats. AICAR treatment reversed the changes of PPARα and phospho-ERK1/2, but increased phospho-p38 MAPK protein level in TAC rats. Similar changes of PPARα and phospho-ERK1/2 protein levels were observed in the hypertrophied cardiomyocytes induced by phenylephrine treatment. Epidermal growth factor (EGF, ERK1/2 activator), but not SB203580 (p38 inhibitor) blocked the up-regulation of PPARα protein level induced by AICAR. Luciferase assay showed that AICAR increased PPARα transcriptional activity which was abrogated by EGF, but not by SB203580. These results demonstrate that AMPK activation enhances the activity of PPARα to inhibit cardiac hypertrophy through ERK1/2, but not p38 MAPK, signaling pathway.
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http://dx.doi.org/10.1016/j.abb.2011.04.010DOI Listing
July 2011

Angiotensin-(1-7) ameliorates myocardial remodeling and interstitial fibrosis in spontaneous hypertension: role of MMPs/TIMPs.

Toxicol Lett 2010 Nov 17;199(2):173-81. Epub 2010 Sep 17.

Department of Cardiology, The Third Hospital, Nanchang, Jiangxi, China.

Angiotensin-(1-7) displays antihypertensive and antiproliferative properties although its effect on cardiac remodeling and hypertrophy in hypertension has not been fully elucidated. The present study was designed to examine the effect of chronic angiotensin-(1-7) treatment on myocardial remodeling, cardiac hypertrophy and underlying mechanisms in spontaneous hypertension. Adult male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were treated with or without angiotensin-(1-7) or the angiotensin-(1-7) antagonist A-779 for 24 weeks. Mean arterial pressure, left ventricular geometry, expression of the hypertrophic markers ANP and β-MHC, collagen contents (type I and III), collagenase (MMP-1), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of MMPs-1 (TIMP-1) were evaluated in WKY and SHR rats with or without treatment. Our data revealed that chronic angiotensin-(1-7) treatment significantly suppressed hypertension, left ventricular hypertrophy, expression of ANP and β-MHC as well as myocardial fibrosis in SHR rats, the effects of which were nullified by the angiotensin-(1-7) receptor antagonist A-779. In addition, angiotensin-(1-7) treatment significantly counteracted hypertension-induced changes in the mRNA expression of MMP-2 and TIMP-1 and collagenase activity, the effects of which were blunted by A-779. In vitro study revealed that angiotensin-(1-7) directly increased the activity of MMP-2 and MMP-9 while decreasing the content of TIMP-1 and TIMP-2. Taken together, our results revealed a protective effect of angiotensin-(1-7) against cardiac hypertrophy and collagen deposition, which may be related to concerted changes in MMPs and TIMPs levels. These data indicated the therapeutic potential of angiotensin-(1-7) in spontaneous hypertension-induced cardiac remodeling.
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http://dx.doi.org/10.1016/j.toxlet.2010.08.021DOI Listing
November 2010

Age-related change of serum angiogenic factor levels in patients with coronary artery disease.

Acta Cardiol 2009 Dec;64(6):735-40

Dept. of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, PR China.

Objective: Vascular endothelial growth factor (VEGF), angiopoietin (Ang)-1 and -2 regulate angiogenesis and might be important in myocardial collateral development. Elevated levels of angiogenic growth factors in patients with coronary artery disease (CAD) have been reported. However, the age-related change of angiogenic growth factors in patients with CAD remains unclear.

Methods And Results: Serum VEGF, Ang-1 and -2 levels were measured by enzyme-linked immunosorbent assay kits. Serum VEGF, Ang-1 and -2 levels in patients with CAD were significantly higher than those in healthy control subjects. In patients aged <61 years and 61 to 70 years, serum Ang-1 and -2 levels were significantly higher than in patients aged >70 years, serum Ang-2 levels in patients aged <61 years were significantly higher than in patients aged from 61 to 70 years. Serum VEGF levels were not significantly different in the three age groups. Serum VEGF, Ang-1 and -2 levels were not significantly different across the age groups in healthy subjects. Regression analysis showed that there was a negative correlation between age and Ang-1 and -2 in patients with CAD.

Conclusion: Serum Ang-1 and -2 levels, but notVEGF levels in patients with CAD, are decreased along with advancing age.
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http://dx.doi.org/10.2143/AC.64.6.2044736DOI Listing
December 2009

Influence of infrasound exposure on the whole L-type calcium currents in rat ventricular myocytes.

Cardiovasc Toxicol 2009 Jun 22;9(2):70-7. Epub 2009 Apr 22.

Department of Pharmacology, Zhongshan Medical College, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.

This study was designed to examine the effect of infrasound exposure (5 Hz at 130 dB) on whole-cell L-type Ca2+ currents (WLCC) in rat ventricular myocytes and the underlying mechanism(s) involved. Thirty-two adult Sprague-Dawley rats were randomly assigned to infrasound exposure and control groups. [Ca2+](i), WLCC, mRNA expression of the a(1c) subunit of L-type Ca2+ channels (LCC), and SERCA2 protein were examined on day 1, 7, and 14 after initiation of infrasound exposure. Fluo-3/AM fluorescence and the laser scanning confocal microscope techniques were used to measure [Ca2+](i) in freshly isolated ventricular myocytes. The Ca2+ fluorescence intensity (FI), denoting [Ca2+](i) in cardiomyocytes, was significantly elevated in a time-dependent manner in the exposure groups. There was a significant increase in WLCC in the 1-day group and a further significant increase in the 7- and 14-day groups. LCC mRNA expression measured by RT-PCR revealed a significant rise in the 1-day group and a significant additional rise in the 7- and 14-day groups compared with control group. SERCA2 expression was significantly upregulated in the 1-day group followed by an overt decrease in the 7- and 14-day groups. Prolonged exposure of infrasound altered WLCC in rat cardiomyocytes by shifting the steady-state inactivation curves to the right (more depolarized direction) without altering the slope and biophysical properties of I (Ca,L). Taken together, our data suggest that changes in [Ca2+](I) levels as well as expression of LCC and SERCA2 may contribute to the infrasound exposure-elicited cardiac response.
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http://dx.doi.org/10.1007/s12012-009-9037-3DOI Listing
June 2009

Infrasound-induced hemodynamics, ultrastructure, and molecular changes in the rat myocardium.

Environ Toxicol 2007 Apr;22(2):169-75

Department of Cardiology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, People's Republic of China.

Recent interest in adverse effects of infrasound on organisms arises from health concerns. We assessed the association between infrasound exposure of 5 Hz at 130 dB and changes of cardiac ultrastructure and function in rats. Thirty-two Sprague-Dawley rats were randomized into control, 1, 7, and 14 days groups for 2 h of infrasound once daily according to planned schedules. Changes of cardiac ultrastructure, hemodynamics indices, intracellular Ca(2+) concentrations ([Ca(2+)](i)), and sarcoplasmic reticulum Ca(2+)-ATPase 2 (SERCA2) were detected. Heart rates in 1 day group were significantly increased compared with control group and no significant changes in other groups. Left ventricular systolic pressures were significantly increased with time. Left ventricular diastolic end pressure and maximum rising rates of left ventricular pressure (+dl/dt) were significantly increased in 7 and 14 days groups and not changed in 1 day group, compared with control group. Maximum dropping rates of left ventricular pressure (-dl/dt) were significantly decreased in 7 and 14 days groups and not changed in 1 day group, compared with control group. In heart cells, there were several swelled mitochondria in 1 day group, more swelled mitochondria in 7 days group, platelet aggregation in the intercellular substance in 14 days group. [Ca(2+)](i) were significantly increased with time. There was a significant increase in SERCA2 in 1 day group, while a significant decrease in 7 and 14 days groups, compared with control group. Infrasound of 5 Hz at 130 dB can damage cardiac ultrastructure and function. Changes of [Ca(2+)](i) and SERCA2 play an important role in the secondary cardiac damage.
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http://dx.doi.org/10.1002/tox.20244DOI Listing
April 2007

Infrasound-induced changes on sexual behavior in male rats and some underlying mechanisms.

Environ Toxicol Pharmacol 2007 Jan 4;23(1):111-4. Epub 2006 Aug 4.

Department of Physical Therapy and Rehabilitation of Xijing Hospital, The Fourth Military Medical University, No. 17, Changle Western Road, Xi'an, Shaanxi Province 710032, PR China.

To investigate some bioeffects of infrasound on copulation as well as underlying mechanisms, we inspected the changes of sexual behavior, serum testosterone concentration and mRNA expression levels of steroidogenic factor 1 (SF-1), steroidogenic acute regulatory protein (StAR) and cytochrome P450 cholesterol side chain cleavage enzyme (P450scc) in testes of rats exposed to infrasound of 8Hz at 90 or 130dB for 1, 7, 14 and 21 days (2h/day), respectively. Rats exposed to 90dB exhibited significant decrement in sexual behavior, serum testosterone levels and mRNA expression levels of StAR and P450scc at the time point of 1 day but not at the rest time points, and no significantly change of SF-1 mRNA expression was observed over the period of 21 days in spite of mild fluctuation. Rats exposed to 130dB exhibited significant decrement in all aspects above, which became more profound with prolonged exposure. Our conclusion is that adverse bioeffects of infrasound on reproduction depend on some exposure parameters, the mechanism of which could involve in the decreased expression of some key enzymes or regulator for testosterone biosynthesis.
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http://dx.doi.org/10.1016/j.etap.2006.07.009DOI Listing
January 2007
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