Molecular mechanisms of endothelial dysfunction in coronary microcirculation dysfunction

Coronary microvascular endothelial cells (CMECs) react to changes in coronary blood flow and myocardial metabolites and regulate coronary blood flow by balancing vasoconstrictors—such as endothelin-1—and the vessel dilators prostaglandin, nitric oxide, and endothelium-dependent hyperpolarizing factor. Coronary microvascular endothelial cell dysfunction is caused by several cardiovascular risk factors and chronic rheumatic diseases that impact CMEC blood flow regulation, resulting in coronary microcirculation dysfunction (CMD). The mechanisms of CMEC dysfunction are not fully understood. However, the following could be important mechanisms: the overexpression and activation of nicotinamide adenine dinucleotide phosphate oxidase (Nox), and mineralocorticoid receptors; the involvement of reactive oxygen species (ROS) caused by a decreased expression of sirtuins (SIRT3/SIRT1); forkhead box O3; and a decreased SK CA /IK CA expression in the endothelium-dependent hyperpolarizing factor electrical signal pathway. In addition, p66Shc is an adapter protein that promotes oxidative stress; although there are no studies on its involvement with cardiac microvessels, it is possible it plays an important role in CMD.