Targeting Arginase 1 but Not Arginase 2 Protects from Myocardial Ischemia–Reperfusion Injury via Nitric Oxide Signaling by Red Blood Cells in Type 2 Diabetes

Background: Arginase influences cardiac tolerance to ischemia–reperfusion by modulating nitric oxide (NO) signaling. In type 2 diabetes (T2D), elevated arginase activity may worsen ischemic injury through red blood cells (RBCs), but the specific roles of arginase isoforms are unclear. Methods: C57BL/6 and db/db mice were pretreated with ARG1 or ARG2 antisense oligonucleotides (ASO) for six weeks. Conditional ARG1 knockout (ARG1fl/fl/Tie2Cretg/−) and wild-type littermates were also studied. Mice underwent coronary artery ligation and reperfusion in vivo for infarct size assessment. In ex vivo experiments, buffer-perfused hearts were subjected to global ischemia–reperfusion with or without RBCs to evaluate recovery of left ventricular developed pressure (LVDP). Results: ARG1 knockdown, but not ARG2, improved post-ischemic recovery of LVDP in isolated hearts. RBCs from ARG1 ASO-treated mice enhanced recovery in wild-type hearts, while ARG1 knockout reduced infarct size compared with controls. Cardioprotection was abolished by NO synthase inhibition. RBCs from male and female ARG1 knockout mice improved LVDP recovery compared with RBCs from wild-type mice. In T2D mice, impaired recovery was restored by ARG1 ASO or RBCs from ARG1 ASO-treated T2D mice. Conclusions: Arginase 1, but not arginase 2, limits cardiac tolerance to ischemia–reperfusion and contributes to increased vulnerability in T2D.