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 β-catenin regulates numerous genes that are associated with cell survival. We therefore investigated Wnt/β-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 β-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/β-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 β-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/β-catenin/ T-cell factor signaling with progressive atherosclerosis, and restoration of WISP-1 protein might be an effective stabilization factor for vulnerable atherosclerotic plaques.
- Received May 2, 2014.
- Accepted August 31, 2014.
- © 2014 American Heart Association, Inc.