Stromal Cell–Derived Factor-1α Confers Protection Against Myocardial Ischemia/Reperfusion Injury

Abstract

Background-Stromal cell-derived factor-1␣ (SDF-1␣) binding to its cognate receptor, CXCR4, regulates a variety of cellular functions such as stem cell homing, trafficking, and differentiation. However, the role of the SDF-1␣-CXCR4 axis in modulating myocardial ischemia/reperfusion injury is unknown. Methods and Results-In mice subjected to ischemic preconditioning, myocardial SDF-1␣ mRNA was found to be increased 3 hours later (PϽ0.05). Myocardial SDF-1␣ and CXCR4 mRNA and protein were found to be expressed in both cardiac myocytes and fibroblasts. SDF-1␣ production increased significantly after 1 or 4 hours of hypoxia and 18 hours of reoxygenation in cultured myocytes (PϽ0.05) but did not change in fibroblast cultures. In isolated myocytes, CXCR4 activation by SDF-1␣ resulted in increased phosphorylation of both ERK 1/2 and AKT and decreased phosphorylation of JNK and p38. Cultured myocytes pretreated with SDF-1␣ were resistant to hypoxia/reoxygenation damage, exhibiting less lactate dehydrogenase release, trypan blue uptake, and apoptotic cell death (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay) (PϽ0.05). This protective effect was blocked by the CXCR4 selective antagonist AMD3100. In vivo, administration of SDF-1␣ before 30 minutes of coronary occlusion followed by 4 hours of reperfusion decreased infarct size (PϽ0.05). The decrease in infarct size with SDF-1␣ administration also was blocked by AMD3100. Conclusions-We conclude that SDF-1␣ and its receptor, CXCR4, constitute a paracrine or autocrine axis in cardiac myocytes that is activated in response to preconditioning and hypoxic stimuli, recruiting the antiapoptotic kinases ERK and AKT and promoting an antiapoptotic program that confers protection against ischemia/reperfusion damage.

Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium

“…In addition, MSCs secrete or express SDF-1α [34,35] and its interaction with CXCR4 increases survival of progenitor cells [6]. SDF-1α could serve as an adhesive molecule by binding CXCR4-expressing cells to the vessel wall [36], which is consistent with our study that a high degree of CXCR4 expression is observed in the vascular endothelial cells. Our results demonstrated that MSCs overexpressing CXCR4 enhanced vascularization in the damaged myocardium.…”

“…Another recent study showed lack of myocytes regeneration by overexpressing SDF-1α in the infarcted area despite improvement of cardiac function [6]. This protection could occur by recruiting the anti-apoptotic kinases ERK and Akt [36]. Our results further suggest that the combined effects of MSCs overexpressing CXCR4 in the infarcted area with secretion of SDF-1α by myocytes are essential for successful cardiac regeneration.…”

SDF-1α stimulates JNK3 activity via eNOS-dependent nitrosylation of MKP7 to enhance endothelial migration

“…S1 A and B). To determine which JNK protein(s) was activated by SDF-1␣ in these cells, we used a previously described assay (22). Exogenous JNK1, JNK2, and JNK3 proteins containing Flag or GFP epitopes were transiently expressed in BAECs and their activities were determined by Western blot analysis with a phospho-JNK antibody after SDF-1␣ treatment.…”

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

“…This function of the CXCR4-CXCL12 axis plays a prominent role in the recruitment of marrow-derived progenitors to the heart after myocardial infarction. 39,40 Currently, there are research efforts to utilize this mechanism by local intramyocardial delivery of a protease-resistant CXCL12 to attract progenitor cells to sites of hypoxic damage after myocardial infarction. 41 Moreover, in hypoxic tumors or in tumors that display mutations in the von Hippel-Lindau tumor suppressor protein pVHL (a negative regulator of HIF-1), HIF-1 upregulates CXCR4 expression, 42,43 providing a survival benefit for tumor cells with high CXCR4 expression.…”