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

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Angiogenesis is regulated by the local balance between angiogenic stimulators and inhibitors and is maintained by muscle-derived angiogenic factors in ischemic tissues. 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. 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. 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.