nitric oxide and endothelial mitochondrial function: Implications for ischemia/reperfusion

The greatest source of nitric oxide (NO) in the normal heart is the endothelial nitric oxide synthase (eNOS), which is localized in vascular endothelial cells (ECs). Endogenously synthesized NO has a variety of physiological functions. Its primary role is thought to be the control of vascular tone via its effect on the soluble guanylate cyclase enzyme of overlying smooth muscle cells. Cytochrome c oxidase (CcO or complex IV), the terminal enzyme in the mitochondrial electron transport chain (ETC) is also a NO target. NO, via its effect on the mitochondrial ETC, can regulate cellular oxygen (O₂) consumption, superoxide radical (O²₂) production, and redox signaling. However, loss of the NO control over respiration can lead to increased formation of reactive O₂ and nitrogen species (ROS/RNS) and mitochondrial damage. Our group is particularly interested on the consequences of the NO interactions with endothelial mitochondria, because ECs under shear stress produce high levels of NO, and endothelial mitochondrial dysfunction is the hallmark of ischemia/reperfusion (I/RP) injury and is common in almost all vascular diseases. In this review, we discuss (1) the NO actions on mitochondria in general, and on mitochondria of cultured ECs exposed to shear stress in particular, and (2) the role of NO on the mitochondrial (dys)function of ECs and cardiomyocytes following I/RP. Using either ex vivo hearts or isolated mitochondria, it has been difficult to understand the relationship between NO, mitochondria and EC function. Cultured EC exposure to conditions of shear stress and O₂ tension (P_o2) that simulate the in vivo I/RP may provide additional insights.