Critical Roles of Cold Shock Domain Protein A as an Endogenous Angiogenesis Inhibitor in Skeletal Muscle

Abstract

Angiogenesis is regulated by the local balance between angiogenic stimulators and inhibitors and is maintained by muscle-derived angiogenic factors in ischemic tissues. Aims: Our objectives were to investigate the effect of cold shock domain protein A (CSDA) as an endogenous angiogenesis inhibitor and to develop a novel strategy of therapeutic angiogenesis by blocking CSDA expression. Results: In human skeletal muscle cells, CSDA was upregulated during hypoxia when cells were damaged and apoptosis was induced. CSDA expression could repress the activity of hypoxia inducible factor-1α and nuclear factor κB, because CSDA can competitively bind the hypoxia response element and the nuclear factor κB-binding element. As a result, vascular endothelial growth factor-A, interleukin-6, and interleukin-8 secretions from skeletal muscle cells were decreased. Further, CSDA depletion increased the secretion level of these angiogenic factors. In a hindlimb ischemia model, transfer of short-hairpin RNA targeting CSDA ameliorated ischemia without direct transfer of angiogenic factors. In this ischemic tissue, vascular endothelial growth factor-A, interleukin-6, and CXCL2 protein levels were increased. Innovation and Conclusion: CSDA appears to play a critical role as an endogenous angiogenesis inhibitor in skeletal muscle, and RNA interference targeting of CSDA is a promising gene therapy strategy for treating peripheral arterial disease. Antioxid. Redox Signal. 15, 2109–2120.