Stromal Cell-Derived Factor-1α Alleviates Calcium-Sensing Receptor Activation-Mediated Ischemia/Reperfusion Injury by Inhibiting Caspase-3/Caspase-9-Induced Cell Apoptosis in Rat Free Flaps

Abstract

Surgical flaps are frequently affected by ischemia/reperfusion (I/R) injury. Calcium-sensing receptor (CaSR) and stromal cell-derived factor-1α (SDF-1α) are closely associated with myocardial I/R injury. This study was performed to evaluate the feasibility of applying SDF-1α to counteract CaSR activation-mediated I/R injury in ischemic free flaps. Free flaps that underwent ischemia for 3 h were equally randomized into five groups: CaCl2, NPS2143 + CaCl2, SDF-1α + CaCl2, AMD3100 + SDF-1α + CaCl2, and normal saline. The free flaps were harvested to evaluate flap necrosis and neovascularization after 2 h or 7 d of reperfusion. p-CaSR/CaSR was extensively expressed in vascular endothelial cells of free flaps after I/R injury, and activation of the SDF-1α/CXCR4 axis and NPS2143 could reduce the expression of cleaved caspase-3, caspase-9, FAS, Cyt-c, and Bax and increase Bcl-2 expression; the opposite was true after CaSR activation. Interestingly, initiation of the SDF-1α/CXCR4 axis might abrogate CaSR activation-induced I/R injury through enhancement of microvessel density. In conclusion, CaSR might become a novel therapeutic target of free flaps affected by I/R injury. Activation of the SDF-1α/CXCR4 axis and NPS2143 could counteract CaSR activation-mediated I/R injury and promote free flap survival through inhibition of caspase-3/caspase-9-related cell apoptosis and enhancement of neovascularization.