Myotrophin induces early response genes and enhances cardiac gene expression

D P Mukherjee, C F McTiernan, S Sen
1993 Hypertension  
We have identified and partially sequenced a soluble factor, myotrophin, from spontaneously hypertensive rat hearts and hypertrophic human hearts that enhances myocyte protein synthesis and stimulates myocardial cell growth. Our studies suggest that myotrophin may be a biochemical link between hemodynamic stress and myocardial cellular hypertrophy. When rat neonatal cardiac myocytes maintained in culture were incubated with myotrophin for 30 minutes, they showed a marked increase in c-myc,
more » ... ease in c-myc, c-fos, and c-jun messenger RNA levels. Cardiac myocytes treated for 24 hours with myotrophin showed a fourfold increase in connexin 43 (gap junction protein), a sixfold increase in atrial natriuretic factor, a threefold increase in skeletal a-actin, and a threefold increase in total myosin transcript levels. Studies on myosin isoforms showed a selective increase in the /3-myosin heavy chain transcript levels but no reciprocal decrease in or-myosin heavy chain transcript levels. Our data suggested that myotrophin appears to be a primary modulator for myocardial cell growth and differentiation and may play an important role in the pathogenesis of cardiac hypertrophy. Myotrophin may be involved in the upregulation of myofibrillar protein and the activation of cardiac gene transcription during growth and hypertrophy of the myocardium, and the induction of early response gene expression may be linked to this response. (Hypertension 1993;21:142-148) KEY WORDS • myotrophin • hypertrophy • RNA, messenger • actins • natriuretic peptides, atrial T he mechanisms involved in the development of myocardial hypertrophy and its regression cannot be fully explained by blood pressure control alone. Studies from our laboratory have provided evidence that factors other than blood pressure control play an important role in the initiation of myocardial hypertrophy in hypertension. 1 Recently we have shown the existence of a factor, "myotrophin," in the myocardium of spontaneously hypertensive rats (SHR) and hypertrophied human hearts that enhances protein synthesis in myocytes in vitro. 2 We have purified this factor to homogeneity and partially sequenced it. An important property of myotrophin is that when added to neonatal rat myocytes maintained in culture, it accelerates myocardial cell growth and increases the number of sarcomeres and gap junction formation. 2 Myoirophin's mechanism of action in modulating myocyte growth is not known. It has been suggested that the jun protein and the products of the c-myc and c-fos genes may be essential to the ability of growth factors to regulate gene transcription. 3 Just as the fos and jun proteins, 4 the myc protein binds to DNA and directly stimulates gene transcription. 5 Several lines of evidence suggest that the
doi:10.1161/01.hyp.21.2.142 pmid:8428777 fatcat:pvjulcbb2rg6jlpxkg2obypz3e