Wnt5a-induced Wnt1-inducible secreted protein-1 suppresses vascular smooth muscle cell apoptosis induced by oxidative stress.

OBJECTIVE: Apoptosis of vascular smooth muscle cells (VSMCs) contributes to thinning and rupture of the atherosclerotic plaque fibrous cap and is thereby associated with myocardial infarction. Wnt protein activation of ß-catenin regulates numerous genes that are associated with cell survival. We therefore investigated Wnt/ß-catenin survival signaling in VSMCs and assessed the presence of this pathway in human atherosclerotic plaques at various stages of the disease process. APPROACH AND RESULTS: Wnt5a induced ß-catenin/T-cell factor signaling and retarded oxidative stress (H2O2)-induced apoptosis in mouse aortic VSMCs. Quantification of mRNA levels revealed a >4-fold (P<0.05; n=9) increase in the expression of the Wnt/ß-catenin responsive gene, Wnt1-inducible secreted protein-1 (WISP-1), which was dependent on cAMP response element-binding protein and sustained in the presence of H2O2. Exogenous WISP-1 significantly reduced H2O2-induced apoptosis by 43% (P<0.05; n=3) and was shown using silencing small interfering RNA, to be important for Wnt5a-dependent survival responses to H2O2 (P<0.05; n=3). WISP-1 protein levels were significantly lower (≈50%) in unstable atherosclerosis compared with stable plaques (n=11 and n=14). CONCLUSIONS: These results indicate for the first time that Wnt5a induces ß-catenin survival signaling in VSMCs via WISP-1. The deficiency of the novel survival factor, WISP-1 in intimal VSMCs of unstable coronary plaques, suggests that there is altered Wnt/ß-catenin/ T-cell factor signaling with progressive atherosclerosis, and restoration of WISP-1 protein might be an effective stabilization factor for vulnerable atherosclerotic plaques.

Emerging regulators of vascular smooth muscle cell function in the development and progression of atherosclerosis.

After a period of relative senescence in the field of vascular smooth muscle cell (VSMC) research with particular regards to atherosclerosis, the last few years has witnessed a resurgence, with extensive research re-assessing potential molecular mechanisms and pathways that modulate VSMC behaviour within the atherosclerotic-prone vessel wall and the atherosclerotic plaque itself. Attention has focussed on the pathological contribution of VSMC in plaque calcification; systemic and local mediators such as inflammatory molecules and lipoproteins; autocrine and paracrine regulators which affect cell-cell and cell to matrix contacts alongside cytoskeletal changes. In this brief focused review, recent insights that have been gained into how a myriad of recently identified factors can influence the pathological behaviour of VSMC and their subsequent contribution to atherosclerotic plaque development and progression has been discussed. An overriding theme is the mechanisms involved in the alterations of VSMC function during atherosclerosis.

Matrix metalloproteinases: influence on smooth muscle cells and atherosclerotic plaque stability.

Atherosclerotic plaque rupture, with subsequent occlusive thrombosis, is the underlying cause of most cases of sudden cardiac death. Matrix metalloproteinases (MMPs) are thought to mediate the progression of stable atherosclerotic lesions to an unstable phenotype that is prone to rupture through the destruction of strength-giving extracellular matrix (ECM) proteins. Smooth muscle cells secrete and deposit ECM proteins and are, therefore, considered protective against atherosclerotic plaque destabilization. However, similar to inflammatory cells (e.g., macrophages), smooth muscle cells release numerous MMPs that are capable of digesting ECM proteins. Thus, the interaction of smooth muscle cells and MMPs in atherosclerotic plaques is complex and not fully understood. Recently, research into the roles of MMPs and their endogenous inhibitors (tissue inhibitors of metalloproteinases), and their effects on smooth muscle behavior during plaque destabilization has been aided by the development of reproducible animal models of plaque instability. A plethora of studies has demonstrated that MMPs directly modulate smooth muscle behavior with both beneficial and deleterious effects on atherosclerotic plaque stability, in addition to their canonical effects on ECM remodeling. Consequently, broad-spectrum MMP inhibition may inhibit plaque-stabilizing mechanisms, such as smooth muscle cell growth, while conversely retarding ECM destruction and subsequent rupture. Hence the development of selective MMP inhibitors, that spare inhibitory effects on smooth muscle cell function, may be useful therapies to prevent plaque rupture and in this regard MMP-12 appears to be a particularly attractive target.

Characteristics of intact and ruptured atherosclerotic plaques in brachiocephalic arteries of apolipoprotein E knockout mice.

The brachiocephalic arteries of fat-fed apolipoprotein E knockout mice develop plaques that frequently rupture and form luminal thromboses. The morphological characteristics of plaques without evidence of instability or with healed previous ruptures (intact) and vessels with acutely ruptured plaques (ruptured) have now been defined, to understand the process of plaque destabilization in more detail. Ninety-eight apolipoprotein E knockout mice were fed a diet supplemented with 21% lard and 0.15% cholesterol, for 5 to 59 weeks. Of these 98 mice, 51 had an acutely ruptured plaque in the brachiocephalic artery. Ruptured and intact plaques differed in terms of plaque cross-sectional area (intact, 0.109+/-0.016 mm2; ruptured, 0.192+/-0.009 mm2; P=0.0005), luminal occlusion (intact, 35.3+/-3.3%; ruptured, 57.7+/-1.9%; P<0.0001), the number of buried caps within the lesion (intact, 1.06+/-0.12; ruptured, 2.66+/-0.16; P<0.0001), fibrous cap thickness (intact, 4.7+/-0.6 microm; ruptured, 2.0+/-0.3 microm; P=0.0004), and lipid fractional volume (intact, 35.9+/-3.0%; ruptured, 50.7+/-2.2%; P=0.0019). This study confirms that plaque rupture is a frequent occurrence in the brachiocephalic arteries of apolipoprotein E knockout mice on a high-fat diet. The data also show that ruptured plaques in these mice show many of the characteristics of vulnerable plaques in humans. This supports the use of this model in studies of the mechanisms and therapy of plaque rupture.