This project will characterize myocardial cellular and molecular biologic events in heart muscle disease (congestive cardiomyopathy, COCM) associated with the acquired immune deficiency syndrome (AIDS). Studies outlined within will explore molecular and subcellular mechanisms of AIDS COCM by testing potential hypotheses of the pathogenesis of COCM in AIDS. Hypothesis 1: AIDS COCM may result from cardiotoxicity of the therapeutic agents used to treat AIDS (or illnesses associated with AIDS). This hypothesis will be tested systematically in vitro using cultured neonatal rat myocardial cells (CMC) exposed to pharmacologic concentrations of agents such as azidothymidine, (AZT). Cardiotoxicity will be monitored (1) by examining alterations of polypeptide synthesis in AZT-exposed CMC, (2) by determining actin polypeptide synthesis and turnover in CMC, (3) by determining actin isoform (alpha, beta, gamma) and isotype (cardiac alpha and skeletal alpha) mRNA expression in CMC exposed to AZT and (4) by localizing Actin mRNA in the CMC exposed to AZT using in situ hybridization techniques. Hypothesis II: AIDS COCM may result from myocarditis secondary to cardiac infection with human immunodeficiency virus (HIV). This will be tested by determining the extent, distribution localization and cell type in the heart which may be infected by HIV using the technique of in situ hybridization, complemented by Southern, Northern, and Western analysis and immunocytochemistry. Other viruses which infect patients with AIDS (such as cytomegalovirus) will also be tested in similar ways. From these combined studies, insight into the pathogenesis and natural history of heart muscle disease associated with AIDS will be obtained.
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