Osteopontin

Abstract

Abstract-The characteristics of dilated cardiomyopathy (DCM) resulting from chronic viral myocarditis are remodeling processes of the extracellular matrix. Based on our findings of enhanced osteopontin (OPN) expression in inflamed human hearts, we further investigated in the murine model of acute and chronic coxsackievirus (CV)B3-myocarditis the role of OPN regarding its involvement in resolution of cardiac virus infection and fibrosis. In hearts of A.BY/SnJ mice susceptible to chronic CVB3-myocarditis, a pronounced increase of OPN expression levels was detected by microarray analysis and quantitative RT-PCR during acute stages of myocarditis. Combined immunohistochemistry and in situ hybridization identified infiltrating macrophages as main OPN producers. In contrast to resistant C57BL/6 and OPN gene-deficient mice, transcription levels of matrix metalloproteinase-3, TIMP1 (tissue inhibitor of metalloproteinases-1), uPA (urokinase-type plasminogen activator), and transforming growth factor ␤1 were elevated in susceptible mice, and as a consequence, procollagen-1␣ mRNA expression and fibrosis was considerably enhanced. Treatment of infected susceptible mice with the vitamin D analog ZK 191784 led to decreased myocardial expression levels of OPN, metalloproteinase-3, TIMP1, uPA, and procollagen-1␣ and subsequently to reduced fibrosis. Concurrently, the fibrosis-relevant signaling molecules pERK (phosphorylated extracellular signal-regulated kinase) and pAkt (phosphorylated Akt), increased in A.BY/SnJ mice, were diminished in ZK 191784 -treated mice. Here, we show that high expression levels of OPN in acute myocarditis are associated with consecutive development of extensive fibrosis that can be reduced by treatment with a vitamin D analog. Thus, OPN may serve as a diagnostic tool as well as a potential therapeutic target to limit cardiac remodeling in chronic myocarditis. Key Words: myocarditis Ⅲ infection Ⅲ inflammation Ⅲ remodeling Ⅲ osteopontin D ilated cardiomyopathy (DCM), which is among the most common heart diseases, has various etiologies and clinical outcomes but is often a sequela of myocarditis and represents a major cause of morbidity and mortality worldwide. Up to 60% of patients with myocarditis and DCM are virus-positive. 1 A critical step in development of DCM is the initiation of remodeling processes of the extracellular matrix. Pathological collagen synthesis leads to interstitial fibrosis and finally to cardiac dysfunction. 2 Characteristics of DCM are left ventricular dilatation, a decreased ejection fraction, and a depressed wall motion attributable to fibrosis. 2 This feature depicts the last stage of inflammatory heart disease, starting with acute myocarditis, passing to chronic myocarditis, and resulting in DCM. 3,4 Viral infections of the heart have been associated with the development of DCM resulting from persistent infection and, consequently, chronic inflammatory processes following acute myocarditis. 4,5 Among the cardiotropic viruses inducing myocarditis, enteroviruses, parvovirus B...

Modulation of endoplasmic reticulum stress and cardiomyocyte apoptosis by mulberry leaf diet in experimental autoimmune myocarditis rats

“…(35) High expression levels of OPN in acute myocarditis are associated with the development of extensive fibrosis. (36) It was reported that quercetin, an antioxidant flavonoid compound found in ML, normalized the calcium movement in transgenic mouse model. (37) In our study, the myocardial level of SERCA2 was significantly decreased and OPN level was increased in the control rats which was found to be normalized in the ML treated group (Fig.…”

Vitamin D and Cardiovascular Disease

“…However, in a murine model of viral myocarditis, a vitamin D analog reduced myocardial fibrosis by inhibition of osteopontin expression. 114 The secretion of atrial natriuretic peptide (which influences proliferation) is also suppressed by 1,25(OH) 2 D, although it is unclear whether this plays a role in any antihypertrophic effect. 62 In addition, the expression of type 1 natiuretic peptide receptor-A, an inhibitor of RAS and myocardial hypertrophy, is increased by 1,25(OH) 2 D. 63 The rate and magnitude of cardiomyocyte sarcomere contraction is modulated by 1,25(OH) 2 D via interaction with caveolin-3 in t-tubules.…”

In vivo T2* weighted MRI visualizes cardiac lesions in murine models of acute and chronic viral myocarditis

“…PA1/08). Four-week-old mice from two mouse strains (SWR/J (H-2q) and ABY/SnJ (H-2b)) were infected with CVB3 Nancy strain as described previously [12,13]. Non-infected animals of both strains served as controls.…”