Abstract 9254: Downregulation of SR Ca2+-ATPase as a Contributing Cause of Impaired Cardiomyocyte Basal and Beta-Adrenergic Regulation of [Ca2+]i with Myocyte Dysfunction in Monkeys with Chronic Heavy Alcohol Consumption
Background. Recent evidence indicates that the main effect of chronic alcohol ingestion is the loss of left ventricle (LV) contractility that progressively induces the development of alcoholic cardiomyopathy (ACM) and heart failure. However, the mechanisms underlying this sequela of events remain unclear. We tested the hypothesis that chronic alcohol-intake-caused progressive LV dysfunction is intrinsic to cardiomyocytes, and that impaired SR Ca2+-ATPase (SERCA 2a) function may play a key role.
Methods. We compared the expression and activity of cardiac SERCA 2a and assessed myocyte contractile, [Ca2+]i transient ([Ca2+]iT) responses to isoproterenol (ISO, 10-8 M), a β-adrenergic receptor (AR) agonist, in isolated myocytes obtained from biopsied LV tissues of cynomolgus monkeys: 6 normal controls (N) and 6 monkeys who chronically self-administered high levels of alcohol (HA) (4% alcohol, 3.3±0.7 g/kg) for 12 months.
Results. Compared with controls, in alcoholic myocytes, SERCA 2a protein expression was decreased 56% (0.50 vs 0.89) and Ca2+-dependent activity of SERCA 2a was decreased 69% (32.7 vs 107.2 nmol/mg protein/min) (p<0.05). This change of SERCA 2a was associated with significant decreases in basal cell systolic amplitude (SA) (79%, HA: 6.4±1.3% vs N: 11.5±1.6%), velocity of shortening (dL/dtmax) (38%, 64.8±5.0 vs 104.8±6.0 μm/s), velocity of relengthening (dR/dtmax) (39%, 54.2±4.7 vs 88.4±5.3 μm/s), and a 34% prolonged time to peak of shortening. In the alcoholic myocytes, the peak [Ca2+]iT (33%, HA: 0.21±0.05 vs N: 0.31±0.05) was significantly reduced, but the diastolic [Ca2+]iT was increased and the decline of [Ca2+]i was slower. These alterations were accompanied by diminished ISO-stimulated positive inotropic effect. Compared with normal controls, in alcoholic cardiomyocytes, ISO (10-8 M) significantly blunted the increases in SA (HA: 27% vs N: 60 %), dL/dtmax (49% vs 79%), dR/dtmax (24% vs 38%) and [Ca2+]iT (16% vs 32%).
Conclusions. Chronic heavy alcohol intake causes downregulation of cardiac SERCA 2a with depressed myocyte contractile performance and abnormal myocyte basal and β-adrenergic regulation of [Ca2+]i. These findings support a mechanistic role of chronic alcohol-induced cardiac SERCA 2a dysfunction in ACM.
- © 2011 by American Heart Association, Inc.