Osteopontin is produced by rat cardiac fibroblasts and mediates A(II)-induced DNA synthesis and collagen gel contraction.

Abstract

Angiotensin II (A II ) is a critical factor in cardiac remodeling which involves hypertrophy, fibroblast proliferation, and extracellular matrix production. However, little is known about the mechanism by which A II accelerates these responses. Osteopontin is an acidic phosphoprotein with RGD (arginine-glycine-aspartate) sequences that are involved in the vascular smooth muscle cell remodeling process. We identified the presence of osteopontin mRNA and protein in cultured rat cardiac fibroblasts and its prominent regulation by A II (10 Ϫ 11 M). Osteopontin message levels were increased fourfold ( P Ͻ 0.01) and protein fivefold ( P Ͻ 0.05) at 24 h after addition of A II (10 Ϫ 7 M). This response was inhibited by the AT 1 receptor blocker, losartan. Osteopontin mRNA levels were increased in hypertrophied ventricles from animals with renovascular hypertension (1.6-fold, P Ͻ 0.05) and aortic banding (2.9-fold, P Ͻ 0.05). To examine the function of osteopontin, we determined its effects on ( a ) the ability of cardiac fibroblasts to contract three-dimensional collagen gels and ( b ) cardiac fibroblast growth. A monoclonal antibody against osteopontin partially blocked A II -induced three-dimensional collagen gel contraction by cardiac fibroblasts (64 Ϯ 4 vs. 86 Ϯ 5% in the presence of antibody, P Ͻ 0.05), while osteopontin itself promoted contraction of the gels by fibroblasts (71 Ϯ 5%, P Ͻ 0.05 compared with control). Either a monoclonal antibody against ␤ 3 integrin which is a ligand for osteopontin or the RGD peptide blocked both A II and osteopontin-induced collagen gel contraction. Thus, the osteopontin RGD sequence binds to ␤ 3 integrins on the fibroblast to promote fibroblast binding to collagen. A II induced a threefold increase in DNA synthesis of cardiac fibroblasts, which was completely blocked by antibodies against osteopontin and ␤ 3 integrin, or by RGD peptide, but not by controls. Thus, A II -induced growth of cardiac fibroblasts also requires osteopontin engagement of the ␤ 3 integrin. Taken together, these results provide the first evidence that osteopontin is a potentially important mediator of A II regulation of cardiac fibroblast behavior in the cardiac remodeling process. ( J. Clin. Invest. 1996. 98:2218-2227.)

Sodium tanshinone IIA sulfonate attenuates angiotensin II-induced collagen type I expression in cardiac fibroblasts in vitro

“…Most of the known effects of Ang II were mediated by AT1 receptors, the expression of which in CFs far exceeded that in cardiomyocytes (Lijnen et al, 2001). Stimulation with Ang II resulted in myocardial fibrosis in vivo (Kim et al, 1995) as well as CFs proliferation and collagen deposition in vitro (Ashizawa et al, 1996). The root of Salvia miltiorrhiza BUNGE, known as Danshen in Chinese, is an herbal plant widely used to cure myocarditis and myocardial infarction (Chen et al, 1979).…”

Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma

“…8 OPN is produced by cardiac fibroblasts in the heart through activation of cardiac AT1R and has a pivotal role in cardiac fibrosis. 9,20 Hypoxic stimulation significantly increased both CTGF and OPN mRNA expression in cardiac fibroblasts, and pretreatment with Telmisartan attenuated this increase. The negative effect of Telmisartan on mRNA expression of CTGF and OPN was blocked by GW9662.…”

Osteopontin: A Protective Mediator of Cardiac Fibrosis?

“…This makes OP an ideal candidate. Various stimuli have been found to induce OP in cardiac cells, including fibroblasts, 3 cardiomyocytes, 4,5 macrophages, endothelial cells, and vascular smooth muscle cells. 6 Angiotensin II (Ang II) is a potent inducer of OP expression in cardiac fibroblasts, in which OP mediates a number of Ang IIdependent cellular functions via binding to ␤ 1 and ␣ v ␤ 3 integrins.…”