Introduction: Peripheral ischemia is associated with higher degree of endothelial dysfunction in coronary district, as well as to worse prognosis after percutaneous coronary interventions.
Hypothesis: to evaluate the effect of peripheral ischemia on arterial remodeling of remote district.
Methods: Male Wistar Rats were randomly divided a group underwent hindlimb ischemia through ligation of the femoral artery (FL), and the other group received no ligation (sham operated). Seven days later, both groups underwent balloon injury (BI) of the carotid artery
Results: Ongoing hindlimb Ischemia significantly enhances neointima formation (neointima/media ratio = 1,58±0,192 versus 1,18±0,138 of control group, n=10), impairs endothelial recovery and increase in infiltration of macrophage cells at 14 days after BI compared to control group. In addition, the expression level of myocardin was markedly decreased, with an up-regulation of inflammatory markers (I-CAM and V-CAM) in the endothelial cells extract. Using real-time polymerase chain reaction, we identified alterations in the expression level of several microRNAs after hindlimb ischemia. In particular, endothelial miR-16 is substantially up regulated, and inhibits the endothelial repair process, down-regulating the Rho GDP dissociation inhibitor α (RhoGDIα) and nitric oxide (NO) production. In particular, we showed that the repression of RhoGDIα, a direct target of miR-16, induces RhoA activation and decreases NO bioavailability. Furthermore, systemic administration of cholesterol-conjugated antagomir-16 reduced neointima formation and improved endothelial recovery in rats with ongoing hindlimb ischemia 14 days after balloon injury (neointima/media ratio = 1,26±0,14 versus 1,63±0,162 of control group; n=7).
Conclusions: Our results indicate that ongoing hindlimb ischemia significantly reduces endothelial recovery and enhances neointimal hyperplasia in a remote injured vascular district. Therapeutic silencing of miR-16 reduces these effects and is a promising approach to prevent adverse arterial remodeling in subjects with peripheral ischemia.