Role of Osteopontin in Cardiac Fibrosis and Remodeling in Angiotensin II-Induced Cardiac Hypertrophy

Abstract

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 ...

Osteopontin: A Protective Mediator of Cardiac Fibrosis?

“…In this issue of Hypertension, Xie et al 12 demonstrate that the loss of OP is responsible for the blunted hypertrophic response leading to early systolic impairment in a model of aortic banding. Their present study confirms findings of a previous report, 13 which observed an impairment of systolic function and onset of left ventricular dilatation in OP Ϫ/Ϫ mice after chronic Ang II infusion to induce myocardial hypertrophy. Interestingly, cardiac hypertrophy measured as heart/body weight ratio was not affected in either of the studies.…”

“…Their study revealed that OP-deficiency did not change the blood pressure response to Ang II-infusion but significantly decreased cardiac fibrosis induced by Ang II. This corresponds to findings of Matsui et al, 13 who found a decrease in cardiac fibrosis in Ang II-induced hypertrophy. Moreover, the effect of OP deficiency on fibrosis was comparable to the treatment of wild-type mice with the aldosterone antagonist eplerenone, which significantly reduced the amount of fibrosis induced by Ang II.…”

“…Therefore, the authors concluded that part of the eplerenone effect could be mediated by inhibition of OP. 13 Surprisingly, in their present study, Xie et al 12 15 reported that the growth and adhesive properties of cardiac fibroblasts from OP Ϫ/Ϫ mice are significantly reduced after chronic Ang II treatment. The effects of OP on cardiomyocyte function are unknown.…”

Teriparatide (Human Parathyroid Hormone (1–34)) Inhibits Osteogenic Vascular Calcification in Diabetic Low Density Lipoprotein Receptor-deficient Mice

“…The data are expressed as the percentage of mineralized area of total valve leaflet area (pixel counts) from digital photomicrograph images, averaging results over five adjacent 5-micron sections for each animal (n ϭ 5-6 animals/treatment arm). Of note, a similar method has now been reported for quantifying vascular calcification in apolipoprotein E Ϫ/Ϫ:OPN Ϫ/Ϫ mice (31). Immunohistochemical visualization of OPN was carried out on 5-micron paraffin sections as previously detailed (15,25).…”

“…Moreover, even though the modest metabolic changes observed (trend for decrease in glucose, percentage of body fat, and leptin levels) were not of statistical significance, the experimental design was underpowered for these specific parameters and may contribute to net physiological responses. Thus, the cell culture models utilized cannot fully recapitulate the role and regulation of OPN in the diabetic vascular disease response, and analyses of mice with cell type-specific OPN deficiency will be required to clarify immunomodulatory versus paracrine versus endocrine contributions (31,51).…”