Exaggerated Left Ventricular Dilation and Reduced Collagen Deposition After Myocardial Infarction in Mice Lacking Osteopontin

Abstract

Abstract-Osteopontin (OPN), an extracellular matrix protein, is expressed in the myocardium with hypertrophy and failure. We tested the hypothesis that OPN plays a role in left ventricular (LV) remodeling after myocardial infarction (MI). Accordingly, OPN expression and LV structural and functional remodeling were determined in wild-type (WT) and OPN knockout (KO) mice 4 weeks after MI. Northern analysis showed increased OPN expression in the infarcted region, peaking 3 days after MI and gradually decreasing over the next 28 days. In the remote LV, OPN expression was biphasic, with peaks at 3 and 28 days. In situ hybridization and immunohistochemical analyses showed increased OPN mRNA and protein primarily in the interstitium. Infarct size, heart weight, and survival were similar in KO and WT mice after MI (PϭNS), whereas the lung wet weight/dry weight ratio was increased in the KO mice (PϽ0.005 versus sham-operated mice). Peak LV developed pressure was reduced to a similar degree after MI in the KO and WT mice. Key Words: extracellular matrix proteins Ⅲ osteopontin Ⅲ collagen Ⅲ myocyte slippage Ⅲ myocyte elongation T he dynamic synthesis and breakdown of extracellular matrix (ECM) proteins may play an important role in myocardial remodeling. 1,2 Recently, using spontaneously hypertensive and aortic-banded rats, we showed increased expression of osteopontin (OPN), an ECM protein, coincident with the development of heart failure. 3 Although first isolated from mineralized bone matrix, OPN has since been shown to be synthesized by several cell types, including cardiac myocytes, microvascular endothelial cells, and fibroblasts. 4 -6 OPN, an adhesive glycophosphoprotein with an arginineglycine-aspartic acid (RGD) sequence, has been shown to interact with integrins (␣ V ␤ 3 , ␣ V ␤ 1 , and ␣ V ␤ 5 ) and the CD44 receptor in an RGD-dependent manner. 4,7 OPN appears capable of mediating diverse biological functions, including cell adhesion, chemotaxis, and signaling. 4,8 OPN has also been shown to interact with fibronectin and collagen, suggesting its possible role in matrix organization and/or stability. 9 -11 Recently, using a mammary cell line, we observed that suppression of OPN synthesis leads to increased activity of matrix metalloproteinase (MMP)-2. 12 In fact, there is increased expression of OPN in several tissues in response to injury, suggesting a role in wound healing. Using a skin incision model, Liaw et al 13 observed disorganization of the matrix and alteration of collagen fibrillogenesis, leading to collagen fibrils with smaller diameters in OPN knockout (KO) mice. Similarly, OPN has been shown to play a critical role in the generation of interstitial fibrosis in the kidney after obstructive nephropathy. 14 Remodeling after myocardial infarction (MI) is associated with left ventricular (LV) dilation, decreased cardiac function, and increased mortality. 15 Early dilation of the LV is likely due to scar expansion in the infarcted region, 16 -18 followed later by progressive remodeling 19 in the noninf...

Association between osteopontin promoter variants and diastolic dysfunction in hypertensive heart in the Japanese population

“…OPN null mice show decreased cardiac function and dilation after MI, indicating beneficial effect of OPN in post-infarct remodeling. 14 In contrast, OPN deletion attenuates cardiac hypertrophy after transverse aortic constriction procedure in mice, 15 suggesting expression of OPN in cardiomyocytes is detrimental in pressure overload. In line with those observation in murine models, cardiac-specific expression of OPN results in dilated cardiomyopathy and premature death with myocyte apoptosis, macrophage infiltration and impaired cardiac conducting system, 16 proposing that cardiac expression of OPN in hypertrophied myocytes mediates systolic and diastolic dysfunction.…”

“…11,12 More recently, OPN has emerged as an important protein involved in cardiovascular diseases, including post-myocardial infarction (MI) remodeling and atherosclerosis. 13,14 OPN is expressed at low level under physiological condition in heart; however, its expression is markedly increased after MI and cardiac hypertrophy. 14,15 Overexpression of OPN in mouse cardiomyocyte induces cardiac dysfunction, dilation and fibrosis in heart, 16 suggesting its expression is closely related to myocardial function and fibrosis.…”

“…14,15 Overexpression of OPN in mouse cardiomyocyte induces cardiac dysfunction, dilation and fibrosis in heart, 16 suggesting its expression is closely related to myocardial function and fibrosis. 14 However, the association of OPN with diastolic function remains to be fully elucidated in the patients with diastolic HF.…”

Transforming growth factor-β receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor

“…The chamber stiffness constant (Kc) was determined by fitting the end-diastolic pressure volume curves from individual hearts to an exponential function. 15,16 The LV chamber stiffness constant (Kc) was determined by fitting the end-diastolic pressure volume curves from individual hearts to an exponential function as described in detail elsewhere. 15,16 In order to measure LV systolic function at a physiological filling pressure, the balloon was deflated to adjust LVEDP to 8-10mmHg, and LV systolic pressure and LVEDP were measured.…”

L’ostéopontine, une molécule aux multiples facettes

“…Mais l'OPN a des effets paradoxaux sur la pathologie cancé-reuse, puisqu'elle semble également inhiber la croissance tumorale, en activant la réponse immune antitumorale TH1 et la différenciation de cellules cytotoxiques antitumorales (réponse immune innée) [31]. L'OPN intervient également dans différentes maladies vasculaires : dans la plaque d'athérome, elle est un inhibiteur naturel de la calcification [32,33] ; dans le coeur, elle est synthétisée par les macrophages après un infarctus [34], ainsi que par les fibroblastes cardiaques et les cellules endothéliales : elle participe à la reconstruction du ventricule gauche en induisant la sécrétion de collagène [35]. Enfin, l'OPN est surexprimée dans le système nerveux au cours de diverses pathologies.…”