Overexpression of alcohol dehydrogenase exacerbates ethanol-induced contractile defect in cardiac myocytes

Abstract

. Overexpression of alcohol dehydrogenase exacerbates ethanol-induced contractile defect in cardiac myocytes. Am J Physiol Heart Circ Physiol 282: H1216-H1222, 2002. First published December 13, 2001; 10.1152/ajpheart.00780.2001.-Alcoholic cardiomyopathy is characterized by impaired ventricular function although its toxic mechanism is unclear. This study examined the impact of cardiac overexpression of alcohol dehydrogenase (ADH), which oxidizes ethanol into acetaldehyde (ACA), on ethanol-induced cardiac contractile defect. Mechanical and intracellular Ca 2ϩ properties were evaluated in ventricular myocytes from ADH transgenic and wild-type (FVB) mice. ACA production was assessed by gas chromatography. ADH myocytes exhibited similar mechanical properties but a higher efficiency to convert ACA compared with FVB myocytes. Acute exposure to ethanol depressed cell shortening and intracellular Ca 2ϩ in the FVB group with maximal inhibitions of 23.3% and 23.4%, respectively. Strikingly, the ethanol-induced depression on cell shortening and intracellular Ca 2ϩ was significantly augmented in the ADH group, with maximal inhibitions of 43.7% and 40.6%, respectively. Pretreatment with the ADH inhibitor 4-methylpyrazole (4-MP) or the aldehyde dehydrogenase inhibitor cyanamide prevented or augmented the ethanol-induced inhibition, respectively, in the ADH but not the FVB group. The ADH transgene also substantiated the ethanol-induced inhibition of maximal velocity of shortening/relengthening and unmasked an ethanol-induced prolongation of the duration of shortening/relengthening, which was abolished by 4-MP. These data suggest that elevated cardiac ACA exposure due to enhanced ADH expression may play an important role in the development of alcoholic cardiomyopathy. transgene; acetaldehyde; shortening; intracellular calcium ion transient CHRONIC ALCOHOLISM causes heart muscle damage leading to the onset of alcoholic cardiomyopathy, which accounts for ϳ33% of dilated cardiomyopathy (6). The incidence of cardiomyopathy is increased up to 50% in patients with chronic alcoholism, and a high proportion of these patients die from cardiac disease. Alcoholic cardiomyopathy is manifested by cardiomegaly, disruptions of the myofibrillary architecture, reduced myocardial contractility, decreased ejection volumes, and enhanced risk of stroke and hypertension (21,27). Clinical studies indicate that alcoholic cardiomyopathy can be reversed by abstinence from alcohol before its progression beyond a certain, as yet poorly defined, point of severity. Diagnosis of alcoholic cardiomyopathy is often made on the basis of deteriorating cardiac function, increased heart size, and a history of alcohol abuse (31). Although several hypotheses have been postulated for the development of alcoholic cardiomyopathy, including direct and indirect cardiotoxicity of alcohol (22) and accumulation of fatty acid ethyl esters (13), no hypothesis has received convincing and consistent clinical and experimental support to be fully validated.Acetaldehyde (ACA), the...

Facilitated ethanol metabolism promotes cardiomyocyte contractile dysfunction through autophagy in murine hearts

“…2,3,25 Our earlier findings revealed that overexpression of ADH in the heart led to enhanced cardiac acetaldehyde exposure and augmented alcohol intake-induced cardiomyopathy manifested as cardiac hypertrophy, protein damage, ER stress, oxidative stress and mitochondrial damage. 9,22,26,27 Results from our current study confirmed cardiac acetaldehyde accumulation had a more pronounced effect in ADH mice (despite comparable levels of blood alcohol and acetaldehyde between FVB and ADH mice) following chronic alcohol intake. More importantly, data from our present study provided evidence for the first time that acetaldehyde through revealed that ethanol/acetaldehyde-induced autophagosome accumulation may be more likely due to an inhibition of the late-stage autophagic flux as opposed to induction of the early-stage autophagosome formation.…”

Influence of Gender on Intrinsic Contractile Properties of Isolated Ventricular Myocytes from Calmodulin‐Induced Diabetic Transgenic Mice

“…Ventricular myocytes were isolated from FVB or OVE26 mouse hearts according to a previously described method (17). In brief, after ketamine-xylazine sedation, mouse hearts were rapidly removed and perfused with Krebs-Henseleit bicarbonate buffer containing (in mM): 118 NaCl, 4.…”

“…The mechanical properties of ventricular myocytes were assessed using a MyoCam 1 video detection system (IonOptix Corporation, Milton, MA) as described previously (17). In brief, cells were placed in a chamber mounted on the stage of an inverted microscope (Olympus IX-70) and superfused with a buffer containing (in mM): 131 NaCl, 4 KCl, 1 CaCl 2 , 1 MgCl 2 , 10 glucose, 10 HEPES, at pH 7.4.…”

“…The 360 nm excitation scan was repeated at the end of the protocol and qualitative changes in intracellular Ca 2þ levels ([Ca 2þ ] i ) were inferred from the ratio of the fura-2 fluorescence intensity (FFI) at the two wavelengths. Fluorescence decay time (t) was also measured as an indication of [Ca 2þ ] i clearing rate (17).…”

In vivo α-adrenergic responses and troponin I phosphorylation: anesthesia interactions

“…We previously showed increased sensitivity to low calcium in perfused hearts from the transgenic mice (13). Avertin is an alcohol-based anesthetic, and alcohol reduces intracellular calcium in mouse myocytes (4). This may explain in part the increased sensitivity to avertin in the transgenic mice, although because dobutamine (which increases intracellular calcium) only partially restores contractility, other effects of avertin are also likely present.…”