The myocardium is composed of myocytes and capillaries which are embedded within an extensive network of connective tissue. In this application we propose to perform a detained investigation of the mechanisms responsible for collagen and other extracellular matrix (ECM) alterations displayed by the hypertrophic myocardium. Two animal models of myocardial hypertrophy will be utilized. These are: 1) Spontaneous Hypertensive Rats (SHR), a model of essential hypertension which resembles the major cause of chronic left ventricular pressure overload in man, and 2) Cardiac hypertrophy induced in rats by abdominal aortic constriction. In addition to study of expression of various extracellular matrix (ECM) genes we will attempt to identify putative regulatory factors such as PDGF, FGF and TGF beta that may be responsible for the initiation and/or perpetuation of the fibrotic response in the hypertrophic myocardium. Using these models we propose: 1) To quantitate the collagen content and characterize the types of collagen occurring during development of acute and chromic hypertrophy. 2) To define by light and electron histochemistry the distribution of normal ECM components (collagen Types I, III, IV, V and VI, laminin and fibronectin) and their changes in hypertrophy. 3) To compare the expression of several ECM genes (as in 2) using recombinant DNA techniques such as Northern and slot-blot and in situ hybridization in normal and hypertrophic myocardium. 4) To examine the mechanisms of increased ECM components in cardiac hypertrophy and to determine if certain growth factors such as TGF beta, PDGF, FGF and IL1 are responsible for stimulation of fibroblast proliferation and or increased production of collagen and other ECM components. We will establish myocardial fibroblast cultures and study the regulation of fibroblast functions (proliferation and biosynthesis) and their modulations by the growth factors. It is hopeful that such studies will help to understand diseases of cardiac hypertrophy and cardiomyopathies.
