INITIATION OF MYOCARDIAL HYPERTROPHY IN HYPERTENSION

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It is established that the mechanism for the initiation and/or regression of myocardial hypertrophy cannot be fully explained by blood pressure control alone. We have shown the evidence for the existence of factor (s) other than blood pressure control that are responsible for an increase in myocardial growth. The hypothesis we want to examine is that development of hypertrophy is initiated by a signal (mechanical or humoral) to the myocardium, which in turn produces a soluble factor that is responsible for triggering protein synthesis and myocardial cell growth. We have identified a soluble factor in the hypertrophied myocardium of spontaneously hypertensive rats (SHR) using myocytes as our bioassay system. The factor has been purified to its homogeneity and partially sequenced. It is a novel peptide with a molecular weight of 12,500 daltons. We have named this factor myotrophin. Recently, we have completed purification and partial sequencing of myotrophin from human cardiomyopathic heart. When myotrophin was added to neonatal cells in culture, the cells showed an enlargement in size that corresponds to a dose-dependent fashion. Furthermore, myotrophin caused a four-fold increased in connexin (gap junction protein) nd a two-fold increase in the total myosin transcript level, associated wit ha selective increase in beta myosin heavy chain expression. At the EM level, myotrophin causes accelerated organization and maturation of the myofibril within 48 hrs. after its addition. More importantly, we have raised specific antibodies against myotrophin and developed a bot blot assay to quantify myotrophin. Our preliminary data showed that myotrophin concentration is increased significantly in the hypertrophied ventricles of SHR and cardiomyopathic human compared to that in normals. Thus suggested that myotrophin may be an important factor in the hypertrophying process. Furthermore, we have isolated a partial cDNA clone for myotrophin and by using a specific probe (RMyo69A), the myotrophin mRNA size was found to be 6 Kb. Our goal for the next five years is to complete the sequencing of and to fully characterized myotrophin, quantity myotrophin (mRNA and protein) in the heart and other tissues during growth and evolution of hypertrophy in SHR and normal pathophysiological significance by determine its role in the initiation and development of cardiac myotrophin may play an important role in the development of hypertrophy. The proposed experiments will demonstrate that myotrophin may be controlling key for the development of cardiac hypertrophy. Continued research may yield information on the mechanism which translates cardiac load and myocardial stress into biochemical messages leading to protein synthesis. Demonstrating the role of myotrophin in initiating myocardial hypertrophy will help in the therapeutic planning for patients with hypertensive heart disease, especially in the development of an appropriate antagonist.