Vascular dysfunction in coronary microcirculation

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Abstract Cardiovascular disease causes 34% of all deaths in the United States and 17.6 million Americans suffer from coronary heart disease (CHD). Of these, 8.5 million experience myocardial infarction. Although we have made significant progress in understanding the mechanisms of reperfusion injury of heart, we are yet to find an effective intervention to alleviate I/R injury. Nitric oxide (NO) plays a major role in relaxation of coronary microcirculation that is important to transport oxygen and nutrients to myocardial tissue. It has been demonstrated that nitric oxide synthase (eNOS), the enzyme that generates NO in the vascular endothelium is altered in I/R and produces deleterious superoxide anion radical, which not only depletes NO by reacting with it, but also produces more harmful reactive nitrogen species. Intriguingly, in our preliminary studies we found that eNOS is glutathionylated and progressively lost in the myocardial tissue following I/R. We hypothesize that eNOS undergoes S-glutathionylation during I/R that induces its chaperone mediated autophagy, resulting in irreversible loss of NO production that affects coronary microcirculation and perfusion resulting in myocardial infarction (MI) in I/R. In Aim 1 we will investigate the mechanism of loss of vascular eNOS due to S- glutathionylation. In Aim 2, we will investigate the specific type of autophagy involved in eNOS disappearance; and in Aim 3 we will elucidate the eNOS autophagy and evaluate whether deglutathionylation by thioredoxin would ameliorate reperfusion injury, using a variety of transgenic and knockout mice models. Our proposed research will provide a clear understanding of the role of coronary vascular mechanism of loss of eNOS in I/R. The results of this study may provide significant insight into clinical management of myocardial infarction and develop new intervention for treatment of reperfusion injury.