Cardiac hypertrophy and remodeling is a common sequela of hypertension and myocardial infarction. These events often culminate in irreversible heart muscle disease similar to congestive cardiomyopathy of a variety of etiologies. The histopathological findings of hypertrophic cardiomyocytes generally includes a characteristic picture of increased cell size and increased cell content of myofibrils. Although the precise subcellular mechanisms of hypertension-induced cardiac hypertrophy is not defined, some of the pathogenic mechanisms include increased RNA and protein synthesis. The induction of these events may be triggered by cytokine stimulation that may involve members of the renin-angiotensin system (RAS), their modulators, and intracellular signaling cascades that alter the levels of gene expression in myocardiocytes. The experiments proposed are designed to test the hypothesis that hypertension leads, in part, to specific effects on the transcriptional regulatory machinery of tissue-specific genes. The studies proposed involve molecular genetic analysis of events related to cytokine effects in cells in culture and in heart muscle in vivo. Some of these experiments are of relatively high risk but have the possibility of providing major understanding of critical mechanisms involved in hypertension induced cardiomyopathy and leading to methods that could ameliorate or prevent it. A long term objective of this proposal is to develop rational therapeutic approaches to cardiac hypertrophy and remodeling, by taking advantage of the knowledge gained from the study of cultured heart cells and myocardium exposed to cytokines. These studies may lead to prevention or reduction of this serious sequela of hypertension. To this end, it is essential to understand the precise molecular mechanisms by which hypertension causes cardiac hypertrophy.
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