LOAD-INDUCED CARDIAC HYPERTROPHY

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The hypothesis upon which this Program Project Grant is based is that hemodynamic loading of the heart is the primary dynamic regulator of the structural and functional properties of adult myocardium. While the predictions of this hypothesis are equally applicable to cardiac physiology and pathophysiology, the central question which I have chosen as the subject of this application is that of how increased load interacts directly with the myocardium as a central factor explaining the causes and consequences of cardiac hypertrophy. Within this context, the five individual projects form a closely interrelated set of studies. In Project #1, Dr. McDermott will use cardiac muscle cells and tissue loaded in vitro, and myocardium loaded in vivo, to define translational control mechanisms which must be of major importance in transducing increased load into the accelerated rate of protein synthesis resulting in net accumulation of cellular protein, the hallmark of hypertrophy. In the companion project, Project #2, Dr. Carabello will build on his studies showing that cardiac hypertrophy is much less in mitral regurgitation than in aortic stenosis by asking what aspect of load presentation to the myocardium may cause a failure to effectively transduce the load signal into protein synthesis. He and Dr. McDermott will work together on studies of protein synthesis and translational control, concerns that are common to both projects. In Project #3, Dr. Menick will take as a point of departure two critical observations of Dr. Kent: initial Na+ entry through stretch-dependent cation channels appears to be an obligatory event in hypertrophy induction, and gene expression for the Na-Ca exchanger is induced very early after cardiac pressure overloading. Since Na-Ca exchanger induction may well be a marker for critical downstream events in the transduction of load into hypertrophy, Dr. Menick will attempt to define molecular mechanisms that regulate the expression of the Na--Ca exchanger gene during hypertrophy induction. In Project #4, Dr. Cooper will use cardiac muscle cells and tissue loaded in vitro and myocardium loaded in vivo to investigate the role that load-induced cytoskeletal alterations may have in the contractile dysfunction of pressure overload cardiac hypertrophy. Since an important role for the microtubules in the contractile dysfunction seen with pressure overload hypertrophy has already been identified, a critical component of this project will be a study of the mechanisms controlling the apparent changes in tubulin stability and/or synthesis. In the companion project, Project #5, Dr. Zile will seek to determine the mechanisms for the abnormal compliance of hypertrophied myocardium at the levels of interstitial changes in cardiac tissue and cytoskeletal changes in the muscle cell. These last two projects will examine the effects of both increased load and any associated neurohumoral changes. Thus the first three projects are concerned with the causes of load-induced cardiac hypertrophy in the adult, with the first two being focused on the induction of increased protein synthesis, and the third being focused on signals for that induction. The last two projects are concerned with the consequences of load-induced cardiac hypertrophy in the adult, with both being focused on ways that changes in structural elements, whether they be extracellular or intracellular, alter the contractile function of the hypertrophied heart.