Novel Mechanisms of Valsartan on the Treatment of Acute Myocardial Infarction Through Inhibition of the Antiadhesion Molecule Periostin

Abstract

Abstract-Our previous study demonstrated that periostin, an extracellular matrix protein, plays an important role in left ventricular remodeling through the inhibition of cell-cell interactions. Because the gene regulation of periostin has not yet been examined, we focused on the effects of angiotensin (Ang) II and mechanical stretch, because Ang II and mechanical stretch are related to cardiac remodeling after myocardial infarction. First, we examined the effects of Ang II on periostin in myocytes and fibroblasts in vitro. Ang II significantly increased periostin through phosphatidylinositol 3-kinase, c-Jun N-terminal kinase, p38, and extracellular signal-regulated kinase 1/2 pathways in myocytes and fibroblasts (PϽ0.05). On the other hand, mechanical stretch also significantly increased periostin expression (PϽ0.05). This increase was inhibited partially, but significantly, by an Ang II receptor blocker, valsartan, and inhibited almost completely by valsartan with the neutralization antibodies for transforming growth factor-␤ and platelet-derived growth factor-BB (PϽ0.05). Therefore, we further examined periostin expression in vivo. Periostin expression was significantly increased in infarcted myocardium (PϽ0.05), and treatment with valsartan significantly attenuated it at 4 weeks after myocardial infarction (PϽ0.05), accompanied by a significant improvement in cardiac dysfunction (PϽ0.05). Overall, the present study demonstrated that Ang II, as well as mechanical stretch, stimulated periostin expression in both cardiac myocytes and fibroblasts, whereas valsartan significantly attenuated the increase in periostin expression. The inhibition of periostin by valsartan might especially contribute to its beneficial effects on cardiac remodeling after myocardial infarction. Key Words: angiotensin II type 1 receptor blockers Ⅲ myocardial infarction Ⅲ adhesions Ⅲ fibrosis Ⅲ ventricular remodeling C ardiac remodeling after myocardial infarction (MI) results in ventricular dysfunction, which contributes to a poor outcome and high mortality. 1 The use of angiotensin (Ang)-converting enzyme inhibitors in patients with MI has improved survival and reduced the rates of major cardiovascular events, 2 and Ang II receptor blockers (ARBs) were expected to prevent cardiac remodeling, like Ang-converting enzyme inhibitors. The Valsartan in Acute Myocardial Infarction Trial demonstrated that an ARB, valsartan, was as effective as a proven regimen of an Ang-converting enzyme inhibitor captopril in improving survival and reducing cardiovascular mortality in patients who suffered an MI. 3,4 Treatment with captopril or valsartan resulted in similar changes in cardiac volume and ejection fraction after MI, 3 whereas treatment with captopril after MI significantly reduced left ventricular (LV) enlargement. 2 On the other hand, periostin is a novel secreted and putative soluble extracellular matrix protein 5 and is known to be expressed in bone and to a lesser extent in lung, kidney, and heart valves but is not found in normal blood vess...

Deletion of periostin reduces muscular dystrophy and fibrosis in mice by modulating the transforming growth factor-β pathway

“…Consistent with this working hypothesis, TGF-β is known to stimulate periostin secretion (11,29), and inhibition of TGF-β leads to decreased periostin expression (7). In both skeletal and cardiac muscle, manipulation of TGF-β via a neutralizing antibody or treatment with losartan leads to improvement in muscle function and histology and, coincidently, a decrease in periostin in the muscle (7,30). These results are consistent with the hypothesis that TGF-β secretion and its enhanced activity contribute to the demise of skeletal muscle in MD (9).…”

Inhibition of Periostin Expression Protects against the Development of Renal Inflammation and Fibrosis

“…23,24 Accordingly, periostin is induced in models of ischemic, hypertensive, and hypertrophic cardiomyopathies, and an angiotensin type 1 receptor antagonist was shown to decrease the cardiac expression of periostin. [25][26][27] Periostin is transiently expressed during renal development, and the expression in the normal adult kidney is low. 28 Our previous results found a strong association between periostin expression and classic indexes of renal function, including proteinuria, plasma creatinine, and renal blood flow.…”

Role of periostin in cancer progression and metastasis: Inhibition of breast cancer progression and metastasis by anti-periostin antibody in a murine model

“…PN1 was up-regulated by extension or angiotensin II in fibroblasts, and increased in myocardial infarction (12). In contrast, inhibition of PN in PN knockout mice which lacked the function of all spliced PN isoforms worsened cardiac function (13,14).…”