Losartan protects against myocardial ischemia and reperfusion injuryviavascular integrity preservation

Vascular hyperpermeability caused by distorted endothelial cell-cell junctions is associated with the no-reflow phenomenon after opening of the occluded vessels in patients with coronary artery disease (CAD), the leading cause of death worldwide. Coronary no-reflow is observed in ∼30% of CAD patients after percutaneous coronary stenting and is associated with a worse prognosis at follow-up and a higher incidence of death. However, limited tools are available to control vascular hyperpermeability and no-reflow. Losartan, an angiotensin II (Ang II) receptor blocker acting on the Ang II type-1 receptor (AT1R) subtype, is a prescription drug for treating hypertension. Here we show that in a murine model of ischemia and reperfusion (I/R), losartan blocked vascular hyperpermeability and decreased infarct size, hemorrhages, edema, and inflammation. Mechanistically, losartan-mediated inhibition of vascular hyperpermeability is mediated by the inhibition of phosphorylation of Src and vascular endothelial Cadherin (VE-cadherin), which increases VEGF receptor 2 (VEGFR2)–Src-VE-cadherin complex formation, resulting in increased cell surface VE-cadherin and inhibition of vascular hyperpermeability. On the other hand, hypoxia and reoxygenation increased the phosphorylation levels of Src and VE-cadherin and reduced the formation of the VEGFR2-Src–VE-cadherin complex, which led to reduced cell surface VE-cadherin and increased vascular hyperpermeability; all were inhibited by losartan. These data suggest that losartan may be used for blocking vascular hyperpermeability associated with I/R.—Li, Y., Yao, Y., Li, J., Chen, Q., Zhang, L., Wang, Q. K. Losartan protects against myocardial ischemia and reperfusion injury via vascular integrity preservation. FASEB J. 33, 8555–8564 (2019). www.fasebj.org