Altered force-frequency response in non-failing hearts with decreased SERCA pump-level.

OBJECTIVE: Decreased SERCA2 activity is considered to significantly contribute to the contractile dysfunction of failing hearts. However, it is now known how decreases in SERCA activity affect cardiac function in detail and also if a decrease alone is sufficient to cause heart failure. METHODS: SERCA2 (+/-) gene-targeted mice (HET) were generated and heart function was analyzed using the isolated work-performing heart technique. Plasma and cardiac catecholamine levels were determined at three, six and nine months of age and heart sections from twelve months old mice subjected to standard histological analysis. RESULTS: We demonstrate that reduced expression of SERCA does not lead to cardiac hypertrophy or fibrosis and does not increase resting plasma-norepinephrine levels in HET mice. However, isolated perfused HET hearts exhibited decreased maximal rates of contraction and relaxation and prolonged time-parameters. The ability of the HET hearts to respond to increases in load (Starling) was not affected and they responded appropriately to beta-adrenergic stimulation. In contrast, the positive force-frequency response found in control hearts was not observed in the HET hearts. The response was flat and three out of five HET hearts failed to maintain work at 550 beats/min. CONCLUSIONS: We conclude that the SERCA2 pump level is a critical positive determinant of cardiac contractility and force-frequency relation.

Differential regulation of p38 mitogen-activated protein kinase mediates gender-dependent catecholamine-induced hypertrophy.

OBJECTIVE: Exogenous catecholamine exposure has been associated with p38 mitogen-activated protein kinase (MAPK) and cardiac hypertrophy. In this study, we investigated the regulation of p38 MAPK in cardiac remodeling elicited by endogenous adrenergic mechanisms. METHODS: Transgenic male and female mice with fourfold phospholamban (PLB) overexpression exhibited enhanced circulating norepinephrine (NE), as a physiological compensatory mechanism to attenuate PLB's inhibitory effects. This enhanced noradrenergic state resulted in left ventricular hypertrophy/dilatation and depressed function. RESULTS: Male transgenics exhibited ventricular hypertrophy and mortality at 15 months, concurrent with cardiac p38 MAPK activation. Female transgenics, despite similar contractile dysfunction, displayed a temporal delay in p38 activation, hypertrophy, and mortality (22 months), which was associated with sustained cardiac levels of MAP Kinase Phosphatase-1 (MKP-1), a potent inhibitor of p38. At 22 months, decreases in cardiac MKP-1 were accompanied by increased levels of p38 activation. In vitro studies indicated that preincubation with 17-beta-estradiol induced high MKP-1 levels, which precluded NE-induced p38 activation. CONCLUSION: These findings suggest that norepinephrine-induced hypertrophy is linked closely with p38 MAP kinase activation, which can be endogenously modulated through estrogen-responsive regulation of MKP-1 expression.