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1.
Biochim Biophys Acta ; 1832(1): 128-41, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22967841

ABSTRACT

Alcohol intake is associated with myocardial contractile dysfunction and apoptosis although the precise mechanism is unclear. This study was designed to examine the effect of the cytochrome P450 enzyme CYP2E1 inhibition on ethanol-induced cardiac dysfunction. Adult male mice were fed a 4% ethanol liquid or pair-fed control diet for 6weeks. Following 2weeks of diet feeding, a cohort of mice started to receive the CYP2E1 inhibitor diallyl sulfide (100mg/kg/d, i.p.) for the remaining feeding duration. Cardiac function was assessed using echocardiographic and IonOptix systems. Western blot analysis was used to evaluate CYP2E1, heme oxygenase-1 (HO-1), iNOS, the intracellular Ca(2+) regulatory proteins sarco(endo)plasmic reticulum Ca(2+)-ATPase, Na(+)Ca(2+) exchanger and phospholamban, pro-apoptotic protein cleaved caspase-3, Bax, c-Jun-NH(2)-terminal kinase (JNK) and apoptosis signal-regulating kinase (ASK-1). Ethanol led to elevated levels of CYP2E1, iNOS and phospholamban, decreased levels of HO-1 and Na(+)Ca(2+) exchanger, cardiac contractile and intracellular Ca(2+) defects, cardiac fibrosis, overt O(2)(-) production, and apoptosis accompanied with increased phosphorylation of JNK and ASK-1, the effects were significantly attenuated or ablated by diallyl sulfide. Inhibitors of JNK and ASK-1 but not HO-1 inducer or iNOS inhibitor obliterated ethanol-induced cardiomyocyte contractile dysfunction, substantiating a role for JNK and ASK-1 signaling in ethanol-induced myocardial injury. Taken together, these findings suggest that ethanol metabolism through CYP2E1 may contribute to the pathogenesis of alcoholic cardiomyopathy including myocardial contractile dysfunction, oxidative stress and apoptosis, possibly through activation of JNK and ASK-1 signaling.


Subject(s)
Alcohol Drinking/adverse effects , Apoptosis , Cardiomyopathies/physiopathology , Cytochrome P-450 CYP2E1/metabolism , Down-Regulation , Myocardial Contraction , Myocytes, Cardiac/physiology , Animals , Cardiomyopathies/complications , Cardiomyopathies/genetics , Cardiomyopathies/metabolism , Cells, Cultured , Cytochrome P-450 CYP2E1/genetics , Cytochrome P-450 CYP2E1 Inhibitors , Ethanol/adverse effects , Ethanol/metabolism , Heme Oxygenase-1/genetics , Heme Oxygenase-1/metabolism , Humans , Male , Mice , Myocytes, Cardiac/cytology , Myocytes, Cardiac/drug effects , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism
2.
Free Radic Biol Med ; 49(7): 1238-53, 2010 Oct 15.
Article in English | MEDLINE | ID: mdl-20678571

ABSTRACT

Chronic alcohol intake leads to the development of alcoholic cardiomyopathy manifested by cardiac hypertrophy and contractile dysfunction. This study was designed to examine the effects of transgenic overexpression of insulin-like growth factor 1 (IGF-1) on alcohol-induced cardiac contractile dysfunction. Wild-type FVB and cardiac-specific IGF-1 mice were placed on a 4% alcohol or control diet for 16weeks. Cardiac geometry and mechanical function were evaluated by echocardiography and cardiomyocyte and intracellular Ca(2+) properties. Histological analyses for cardiac fibrosis and apoptosis were evaluated by Masson trichrome staining and TUNEL assay, respectively. Expression and phosphorylation of Cu/Zn superoxide dismutase (SOD1), Ca(2+) handling proteins, and key signaling molecules for survival including Akt, mTOR, GSK3beta, Foxo3a, and the negative regulator of Akt, phosphatase and tensin homolog on chromosome 10 (PTEN), as well as mitochondrial proteins UCP-2 and PGC1alpha, were evaluated by Western blot analysis. Chronic alcohol intake led to cardiac hypertrophy, interstitial fibrosis, reduced mitochondrial number, compromised cardiac contractile function and intracellular Ca(2+) handling, decreased SOD1 expression, elevated superoxide production, and overt apoptosis, all of which, with the exception of cardiac hypertrophy, were abrogated by the IGF-1 transgene. Immunoblotting data showed reduced phosphorylation of Akt, mTOR, GSK3beta, and Foxo3a; upregulated Foxo3a and PTEN; and dampened SERCA2a, PGC1alpha, and UCP-2 after alcohol intake. All these alcohol-induced changes in survival and mitochondrial proteins were alleviated by IGF-1. Taken together, these data favor a beneficial role for IGF-1 in alcohol-induced myocardial contractile dysfunction independent of cardiac hypertrophy.


Subject(s)
Cardiomyopathy, Alcoholic/metabolism , Ethanol/administration & dosage , Heart/drug effects , Insulin-Like Growth Factor I/metabolism , Myocardium , Animals , Apoptosis/drug effects , Apoptosis/genetics , Cardiomyopathy, Alcoholic/genetics , Cardiomyopathy, Alcoholic/pathology , Cardiomyopathy, Alcoholic/physiopathology , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Heart/anatomy & histology , Heart/physiology , Hypertrophy , Insulin-Like Growth Factor I/genetics , Mice , Mice, Transgenic , Myocardial Contraction/drug effects , Myocardial Contraction/genetics , Myocardium/metabolism , Myocardium/pathology , Organ Specificity , PTEN Phosphohydrolase/biosynthesis , PTEN Phosphohydrolase/genetics , Proto-Oncogene Proteins c-akt/metabolism , Superoxide Dismutase/biosynthesis , Superoxide Dismutase/genetics , Superoxide Dismutase-1 , TOR Serine-Threonine Kinases/metabolism , Transgenes/genetics
3.
Cell Biochem Biophys ; 42(1): 1-12, 2005.
Article in English | MEDLINE | ID: mdl-15673924

ABSTRACT

Hypertension leads to impaired contractile function. This study examined the impact of inhibition of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) by thapsigargin or cyclopiazonic acid (CPA) on cardiac contractile function in ventricular myocytes from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Mechanical properties were examined including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR90), and maximal velocity of shortening/relengthening (+/-dL/dt). Intracellular Ca2+ transients were evaluated as fura-2 fluorescent intensity (FFI), excitation-induced change in FFI (DeltaFFI = peak-basal), and fluorescence decay rate (tau). Expression of Ca2+ regulatory proteins SERCA2a, Na+-Ca2+ exchanger (NCX), and phospholamban (PLB) were assessed by reverse transcriptase polymerase chain reaction and Western blot. SHR rats exhibited elevated blood pressure. SHR myocytes displayed decreased PS +/- dL/dt, peak FFI, and DeltaFFI; shortened TPS; prolonged tau with normal TR90; and basal FFI compared with WKY myocytes. Inhibition of SERCA with thapsigargin (5 microM) or CPA (10 microM) significantly depressed PS +/- dL/dt, baseline FFI, and DeltaFFI, and prolonged TPS, TR90, and tau in WKY myocytes. However, SHR myocytes were relatively insensitive to thapsigargin or CPA with only TPS and TR90 prolonged. Both mRNA and protein expressions of NCX and PLB were significantly enhanced, whereas SERCA2a protein abundance was reduced in SHR rats compared with the WKY group. Our data suggest that inhibition of SERCA function differentially affected cardiac contractile function in ventricular myocytes from normotensive and hypertensive rats possibly through reduced SERCA2a, elevated PLB, and NCX expression under hypertension.


Subject(s)
Calcium-Transporting ATPases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Hypertension/pathology , Myocardial Contraction/drug effects , Myocytes, Cardiac/drug effects , Thapsigargin/pharmacology , Animals , Calcium-Binding Proteins/metabolism , Calcium-Transporting ATPases/metabolism , Cells, Cultured , Gene Expression , Heart Ventricles/cytology , Indoles/pharmacology , Intracellular Fluid/metabolism , Myocardial Contraction/physiology , Myocardium/cytology , Myocytes, Cardiac/physiology , Rats , Rats, Inbred SHR
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