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YIA 4 Wnt5a signalling promotes VSMC survival via WISP-1: consequences for VSMC viability in atherosclerotic plaques
  1. C Mill,
  2. J Y Jeremy,
  3. S J George
  1. Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Bristol, UK

Abstract

Apoptosis of vascular smooth muscle cells (VSMCs) within the fibrous cap of atherosclerotic plaques causes cap thinning and thereby plaque rupture and myocardial infarction. Identification of novel mechanisms that regulate VSMC survival may be useful for designing treatments to increase plaque stability. In this study we show that Wnt5a, a member of the Wnt family, induces β-catenin signalling in mouse primary VSMCs and retards oxidative stress (H2O2)-induced VSMC apoptosis. Therefore we aimed to determine the mechanism underlying Wnt5a-induced VSMC survival.

We observed that Wnt5a modulates the mRNA expression of the Wnt/β-catenin responsive gene Wnt1 inducible secreted protein (WISP)-1 (4.17±1.5 fold (n=8, p<0.05)). However, unlike other Wnt/β-catenin responsive genes investigated (eg, IGF-1, WISP-2), WISP-1 mRNA levels remained elevated in the presence of oxidative stress induced by H2O2 (5.05±2.3-fold (n=8, p<0.05). Additionally, recombinant WISP-1 protein rescued VSMCs from H2O2 induced apoptosis (9.54±1.5 vs 16.8±2.2 n=3 p<0.05). Wnt5a-dependent survival responses to H2O2 were lost following silencing of WISP-1 in VSMC using siRNA (4.9±1 vs 10.9±2 n=7 p<0.05). To establish the relevance of these findings to atherosclerosis we performed immunohistochemistry for Wnt5a and WISP-1 in human coronary atherosclerotic plaques. We observed that Wnt5a protein was significantly increased by 65% with atherosclerosis progression (unstable 18.4%±2.5% vs stable 6.5%±1.4% Wnt5a positive area, p<0.001, n=10). In addition, we show for the first time that WISP-1 is expressed in advanced human coronary artery lesions but interestingly appears to be absent in Wnt5a-positive intimal VSMCs. In conclusion this data shows that WISP-1 is regulated by Wnt5a in VSMC and retards VSMC apoptosis induced by oxidative stress. The deficiency of the novel survival factor, WISP-1 in intimal VSMCs of coronary plaques may provoke VSMC apoptosis resulting in plaque instability.

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