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Transforming Growth Factor-β Blockade Down-Regulates the Renin-Angiotensin System and Modifies Cardiac Remodeling after Myocardial Infarction

Christchurch Cardioendocrine Research Group (L.J.E., N.J.A.S., A.P.P., T.G.Y., A.M.R., V.A.C.), Department of Medicine, Christchurch School of Medicine and Health Sciences, Christchurch 8140, New Zealand; SCIOS Inc. (S.M., A.A.P.), Fremont, California 94555; and Department of Cardiology (P.G.B.), Christchurch Hospital, Christchurch 8011, New Zealand

Address all correspondence and requests for reprints to: Dr. L. J. Ellmers, Ph.D., Department of Medicine, Christchurch School of Medicine and Health Sciences, P.O. Box 4345, Christchurch 8140, New Zealand. E-mail: leigh.ellmers{at}chmeds.ac.nz.

After myocardial infarction (MI), the heart may undergo progressive ventricular remodeling, resulting in a deterioration of cardiac function. TGF-β is a key cytokine that both initiates and terminates tissue repair, and its sustained production underlies the development of tissue fibrosis, particularly after MI. We investigated the effects of a novel orally active specific inhibitor of the TGF-β receptor 1 (SD-208) in an experimental model of MI. Mice underwent ligation of the left coronary artery to induce MI and were subsequently treated for 30 d after infarction with either SD-208 or a vehicle control. Blockade of TGF-β signaling reduced mean arterial pressure in all groups. SD-208 treatment after MI resulted in a trend for reduced ventricular and renal gene expression of TGF-β-activated kinase-1 (a downstream modulator of TGF-β signaling) and a significant decrease in collagen 1, in association with a marked decrease in cardiac mass. Post-MI SD-208 treatment significantly reduced circulating levels of plasma renin activity as well as down-regulating the components of the cardiac and renal renin-angiotensin system (angiotensinogen, angiotensin converting enzyme, and angiotensin II type I receptor). Our findings indicate that blockade of the TGF-β signaling pathway results in significant amelioration of deleterious cardiac remodeling after infarction.