Abstract-Osteopontin (OPN) is upregulated in several experimental models of cardiac fibrosis and remodeling. However, its direct effects remain unclear. We examined the hypothesis that OPN is important for the development of cardiac fibrosis and remodeling. Moreover, we examined whether the inhibitory effect of eplerenone (Ep), a novel aldosterone receptor antagonist, was mediated through the inhibition of OPN expression against cardiac fibrosis and remodeling. Wild-type (WT) and OPN-deficient mice were treated with angiotensin II (Ang II) for 4 weeks. WT mice receiving Ang II were divided into 2 groups: a control group and an Ep treatment group. Ang II treatment significantly elevated blood pressure and caused cardiac hypertrophy and fibrosis in WT mice. Ep treatment and OPN deficiency could reduce the Ang II-induced elevation of blood pressure and ameliorate the development of cardiac fibrosis, whereas Ep-only treatment abolished the development of cardiac hypertrophy. Most compelling, the reduction of cardiac fibrosis led to an impairment of cardiac systolic function and subsequent left ventricular dilatation in Ang II-treated OPN-deficient mice. These results suggest that OPN has a pivotal role in the development of Ang II-induced cardiac fibrosis and remodeling. Moreover, the effect of Ep on the prevention of cardiac fibrosis, but not cardiac hypertrophy, might be partially mediated through the inhibition of OPN expression. Osteopontin (OPN) is reported to be involved in the process of Ang II-induced fibrosis. 3 Furthermore, OPN can interact with various extracellular matrices, including fibronectin and collagen, suggesting its possible role in matrix organization and stability. 4 Recently, it was shown that OPN expression in heart was associated with the development of heart failure. 5 Moreover, in a murine model of myocardial infarction, OPN deficiency caused exaggeration of left ventricular (LV) dilation and reduction of collagen deposition compared with wild-type (WT) mice. 6 These results suggest that OPN has a pivotal role in cardiac fibrosis and cardiac remodeling.More recently, an important link was suggested in Ang II-induced cardiac fibrosis between OPN and Ald. Ang II induced inflammatory damage in coronary arteries and OPN expression, and eplerenone (Ep), a novel Ald receptor antagonist, could inhibit the OPN expression and ameliorate the Ang II-induced inflammatory damage to coronary arteries. 7 These results suggested that (1) OPN-mediated vascular inflammation might be part of the mechanism by which the renin-angiotensin-aldosterone system participates in the development of cardiac fibrosis and (2) the effect of Ep on the inhibition of vascular inflammation might be modulated by suppressing OPN expression.To investigate whether OPN plays a pivotal role in cardiac fibrosis and remodeling, we treated OPN-deficient (OPN Ϫ/Ϫ ) mice with Ang II and compared them with WT mice treated with Ang II alone or with Ang II and Ep. Herein, we report the role of OPN and the relationship between OPN and Ald ...
Objective-Osteopontin (OPN), a noncollagenous adhesive protein, is implicated in atherosclerosis, in which macrophages within atherosclerotic plaques express OPN. However, it is not known whether the elevated OPN expression is a cause or result of atherosclerosis. Methods and Results-We generated mice that lacked OPN and crossed them with apolipoprotein (apo) E-deficient mice and analyzed these mice with a mixed C57BL/6ϫ129 background after 36 weeks on a normal chow diet. In female mice, OP ϩ/Ϫ E Ϫ/Ϫ and OP Ϫ/Ϫ E Ϫ/Ϫ mice had significantly smaller atherosclerotic and inflammatory lesions compared with OP ϩ/ϩ E Ϫ/Ϫ mice, and that was reflected by smaller area of MOMA-2-positive staining. In male mice, however, there was no significant difference in the atherosclerosis lesion areas among 3 genotypes. In both OP Ϫ/Ϫ E Ϫ/Ϫ and OP ϩ/ϩ E Ϫ/Ϫ mice, typical atherosclerotic lesions were detected, which include necrotic core, foamy cell collections, and cholesterol clefts. However, we found that vascular mineral-deposited areas in 60-week-old male OP Ϫ/Ϫ E Ϫ/Ϫ mice were significantly increased compared with those in OP ϩ/ϩ E Ϫ/Ϫ male mice. Key Words: osteopontin Ⅲ atherosclerosis Ⅲ macrophage Ⅲ calcification Ⅲ lipid metabolism A therosclerosis is characterized as a chronic inflammatory process of the vessel wall. Atherosclerosis is initiated by the infiltration of monocytes and T-lymphocytes into activated endothelium, followed by their migration into the intima and subsequent lipid accumulation within macrophages. In late stages of atherosclerosis, calcification is a common advanced complication. Osteopontin (OPN), a noncollagenous adhesive protein, was first found at sites of dystrophic calcification and is synthesized at high levels by macrophages in calcified aortic valves and atherosclerotic plaques. 1 The expression of OPN protein was detected in not only macrophages but also vascular smooth muscle cells within atherosclerotic lesion. [1][2][3][4][5] In addition, it was shown that vascular smooth muscle cells during the proliferative and migratory phase, but not the quiescent and contractile phase, expressed OPN in a model of balloon catheter injury of rat carotid artery. 2 More importantly, Liaw et al 6 reported that neutralizing antibodies directed against OPN inhibited rat carotid neointimal thickening after endothelial denudation. Taken together, these results suggested that OPN can play a pivotal role in the early stage of atherosclerosis, including proliferation and migration of smooth muscle cells as well as at the late stage of atherosclerosis, characterized by calcified atheromatous plaque formation. Conclusions-TheseTo more directly address the question of whether OPN initiates the development of atherosclerotic lesion and plays a role in calcification, we took advantage of OPN-deficient mice we had recently generated. 7 We crossed them with apolipoprotein (apo) E-deficient mice and made OPN and apoE double-deficient mice. In mice deficient for OPN gene expression, OPN mRNA was not detected in any organs. ...
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