CD38 Genetic Knockout Confers Marked Protection Against In Vivo Myocardial Ischemia/Reperfusion Injury

Abstract

Background CD38 is a multifunctional membrane protein with the major NAD(P)ase activity in human tissues. It is highly expressed in endothelial cells and some inflammatory cells. Using ex vivo perfused hearts and cell models, we have shown that ischemia/reperfusion (I/R) in the heart leads to CD38 activation with subsequent NAD(P)H depletion and impaired endothelial nitric oxide synthase function, triggering diminished coronary flow and decreased contractile function. Here we test if genetic knockout (KO) of CD38 protects against in vivo myocardial I/R in mice. Methods Male CD38 KO (n=7) and wild type (WT) mice (n=11) in C57BL/6 background were subjected to I/R surgery at the age of 12–16 weeks. The mice were anesthetized, endotracheal intubated, and ventilated with a rodent ventilator. A left lateral thoracotomy was performed, and the left anterior descending coronary artery was visualized and ligated with a slip knot. Then, mice were subjected to 30 minutes of ischemia followed by 24 h of reperfusion. The left ventricular area at risk (AAR) and infarct areas were visualized by Evans blue and TTC staining, respectively. The hearts were sliced and digitally photographed. Left ventricular AAR and infarct area were contoured using Image J software. (P<0.05) was considered significant in statistical testing. Results In CD38 KO and WT mice the AAR/LV % was similar with values of 56.2±6.8 % and 54.6±4.4 %, respectively. However, CD38 KO mice exhibited marked protection against myocardial I/R injury with decreased infarction. Infarct area/AAR was only 10.3±3.2 % in CD38 KO mice compared to 36.7±6.8 % in WT, p=0.0097. Conclusions Thus, abrogation of CD38 expression was observed to be highly protective against in vivo myocardial I/R injury with major reduction in infarction. As new highly potent CD38 inhibitors have recently been developed, these may hold great promise as therapeutics in the treatment of unstable coronary syndromes and acute myocardial infarction.