Molecular etiologies of heart failure, an emerging cardiovascular epidemic affecting 4.7 million Americans and costing 17.8 billion health-care dollars annually, remain poorly understood. Here we report that an inherited human dilated cardiomyopathy with refractory congestive heart failure is caused by a dominant Arg --> Cys missense mutation at residue 9 (R9C) in phospholamban (PLN), a transmembrane phosphoprotein that inhibits the cardiac sarcoplasmic reticular Ca2+-adenosine triphosphatase (SERCA2a) pump. Transgenic PLN(R9C) mice recapitulated human heart failure with premature death. Cellular and biochemical studies revealed that, unlike wild-type PLN, PLN(R9C) did not directly inhibit SERCA2a. Rather, PLN(R9C) trapped protein kinase A (PKA), which blocked PKA-mediated phosphorylation of wild-type PLN and in turn delayed decay of calcium transients in myocytes. These results indicate that myocellular calcium dysregulation can initiate human heart failure-a finding that may lead to therapeutic opportunities.
Cardiac hypertrophy is a common response to injury and hemodynamic stress and an important harbinger of heart failure and death. Herein, we identify the Kruppel-like factor 15 (KLF15) as an inhibitor of cardiac hypertrophy. Myocardial expression of KLF15 is reduced in rodent models of hypertrophy and in biopsy samples from patients with pressure-overload induced by chronic valvular aortic stenosis. Overexpression of KLF15 in neonatal rat ventricular cardiomyocytes inhibits cell size, protein synthesis and hypertrophic gene expression. KLF15-null mice are viable but, in response to pressure overload, develop an eccentric form of cardiac hypertrophy characterized by increased heart weight, exaggerated expression of hypertrophic genes, left ventricular cavity dilatation with increased myocyte size, and reduced left ventricular systolic function. Mechanistically, a combination of promoter analyses and gel-shift studies suggest that KLF15 can inhibit GATA4 and myocyte enhancer factor 2 function. These studies identify KLF15 as part of a heretofore unrecognized pathway regulating the cardiac response to hemodynamic stress.
Cardiac hypertrophy and dilatation can result from stimulation of signal transduction pathways mediated by heterotrimeric G proteins, especially G q , whose ␣ subunit activates phospholipase C (PLC). We now report that transient, modest expression of a hemagglutinin (HA) epitope-tagged, constitutively active mutant of the G q ␣ subunit (HA␣* q ) in hearts of transgenic mice is sufficient to induce cardiac hypertrophy and dilatation that continue to progress after the initiating stimulus becomes undetectable. At 2 weeks, HA␣ * q protein is expressed at less than 50% of endogenous ␣ q͞11 , and the transgenic hearts are essentially normal morphologically. Although HA␣ * q protein declines at 4 weeks and is undetectable by 10 weeks, the animals develop cardiac hypertrophy and dilatation and die between 8 and 30 weeks in heart failure. As the pathology develops, endogenous ␣ q͞11 rises (2.9-fold in atria; 1.8-fold in ventricles). At 2 weeks, basal PLC activity is increased 9-to 10-fold in atria but not ventricles. By 10 weeks, it is elevated in both, presumably because of the rise in endogenous ␣ q͞11 . We conclude that the pathological changes initiated by early, transient HA␣ * q expression are maintained in part by compensatory changes in signal transduction and other pathways.
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