The overall objective of this project is to study the underlying mechanisms in the development and regression of myocardial hypertrophy in hypertension. Our laboratory has shown that the development/regression of cardiovascular hypertrophy does not depend on mechanical load alone but on the interplay of many aspects: cardiac pressure load, the cardioadrenergic system, and various humoral factors. In the past funding period we have shown that several factors can modulate myosin isoform during the regression of hypertrophy. Influential factors are dietary sodium, catecholamines, and many pharmacological agents used as antihypertensive drugs. We have also shown that the shifting of myosin isoforms is independent of blood pressure, myocardial mass and sympathetic activity. These observations generated new questions, and we have designed this renewal proposal to study the structural remodeling of the interstitial matrix during the progressive development of hypertrophy in hypertension. Excess collagen accumulations are known to increase the heart's rigidity, compromising its function and leading to failure. Our preliminary data showed that collagen has various phenotypic forms and that in the development of hypertrophy an important indicator of heart stiffness is the relative abundance of a specific collagen type, in addition to collagen quantity. As to whether regression of hypertrophy is beneficial or harmful, two key concepts in post hypertrophic regression have never been established: the functional consequences of collagen alteration, and the capacity of the newly reduced small heart to handle sudden pressure overload. Results from our study also suggest that each antihypertensive drug has a unique effect on the biochemical composition of the heart, e.g., collagen, and our data showed that functional consequences will vary according to the type of collagen or myosin present. In the next 5 years we will focus on the heart's collagen production, determining whether regression of hypertrophy is beneficial or harmful. We propose to examine the hypothesis that functional and structural remodelling of the heart's interstitial matrix in hypertrophy and heart failure and the heart's re-remodelling after regression are associated with alterations in collagen production, which plays a role in influencing cardiac function. We will study collagen and its phenotypes at cellular and molecular levels, evaluating collagen's functional consequences.
Our specific aims are a) to quantify collagen and its phenotypes, identifying changes in the mRNA level and measuring the transcription rate of each phenotype; b) to determine the effect of pharmacologic intervention on the above parameters; c) to elucidate the mechanism for altered collagen production in cultured myocardial fibroblasts and myocytes; d) to evaluate whether regression of hypertrophy by antihypertensive therapy (alpha-methyldopa, captopril, atenolol) is beneficial or harmful. These studies will outline the abnormalities of collagen metabolism in the development/regression of myocardial hypertrophy and elucidate their effect on cardiac function. On identifying the derangement, we will determine if appropriate treatment corrects the changes and if such directed alteration in myocardial collagen formation improves the compromised function of the hypertrophied heart.
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