The objective of this proposal is to define the alterations in myocardial protein metabolism that regulate the responses to acute and chronic volume overload in an intact animal model of aortic regurgitation. The relative contributions of cardiac protein synthesis and degradation to the structural remodelling that occurs during the development of left ventricular dilatation and eccentric hypertrophy will be examined. The effects of the severity and chronicity of volume overload on synthesis and degradation rates of total cardiac protein, individual myofibrillar proteins and collagen will be investigated. The hypothesis to be tested is that specific and total cardiac protein degradation rates as well as synthesis rates are fundamentally important to the regulation of cardiac protein mass during the left ventricular dilation and eccentric hypertrophy that develop in response to chronic volume overload. Thus we will examine the biochemical mechanisms underlying the structural and functional responses to chronic aortic regurgitation. The process of testing our hypothesis can be expected to improve understanding of cardiac protein regulation in vivo. Specifically, it is hoped that these studies may allow identification of protein metabolic abnormalities that could prove useful as indices of degeneration for timing of valve replacement, or which might provide insights helpful in the design of new therapeutic approaches to retarding the effects of volume loading.
