Vasomotor regulation of coronary microcirculation by oxidative stress: Role of arginase

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Abstract

Overproduction of reactive oxygen species, i.e., oxidative stress, is associated with the activation of redox signaling pathways linking to inflammatory insults and cardiovascular diseases by impairing endothelial function and consequently blood flow dysregulation due to microvascular dysfunction. This review focuses on the regulation of vasomotor function in the coronary microcirculation by endothelial nitric oxide (NO) during oxidative stress and inflammation related to the activation of l-arginine consuming enzyme arginase. Superoxide produced in the vascular wall compromises vasomotor function by not only scavenging endothelium-derived NO but also inhibiting prostacyclin synthesis due to formation of peroxynitrite. The upregulation of arginase contributes to the deficiency of endothelial NO and microvascular dysfunction in various vascular diseases by initiating or following oxidative stress and inflammation. Hydrogen peroxide, a diffusible and stable oxidizing agent, exerts vasodilator function and plays important roles in the physiological regulation of coronary blood flow. In occlusive coronary ischemia, the release of hydrogen peroxide from the microvasculature helps to restore vasomotor function of coronary collateral microvessels with exercise training. However, excessive production and prolonged exposure of microvessels to hydrogen peroxide impairs NO-mediated endothelial function by reducing l-arginine availability through hydroxyl radical-dependent upregulation of arginase. The redox signaling can be a double-edged sword in the microcirculation, which helps tissue survival in one way by improving vasomotor regulation and elicits oxidative stress and tissue injury in the other way by causing vascular dysfunction. The impact of vascular arginase on the development of vasomotor dysfunction associated with angiotensin II receptor activation, hypertension, ischemia-reperfusion, hypercholesterolemia, and inflammatory insults is discussed.A normal function of the vascular endothelium involving responses to physical (1), chemical (2, 3), and electrical (4, 5) stimuli is essential to maintain microvascular homeostasis and regulate local blood flow by changing vasomotor activity via release of endothelium-derived vasodilators, e.g., nitric oxide (N O), prostacyclin (PGI2), C-type natriuretic peptide, and hyperpolarizing factors (EDHF). The endothelium also releases vasoconstrictors such as endothelin-1, prostaglandin H/F, thromboxane, and angiotensin. Endothelial dysfunction is one of the earliest markers of vascular abnormalities observed in many cardiovascular diseases associated with oxidative stress due to excessive production of reactive oxygen species (ROS). Redox regulation of proteins by moderate levels of ROS is indispensable for signaling pathways underlying the regulation of subcellular and cellular activity as well as cardiovascular function (6-8). Notably, superoxide and hydrogen peroxide (H2O2) are the most common and important ROS involved in the physiological and pathophysiological events (6-8). Superoxide is produced by several enzyme systems in the cell and it is converted to H2O2 by superoxide dismutase. H2O2 itself is a potent oxidizing agent that can be converted to hydroxyl radical in the presence of ferric compounds. H2O2 can be degraded by catalase to form H2O and an oxygen molecule. Compared with superoxide, H2O2 is stable, lacks charge, has longer half-life, is cell permeable, and can diffuse across longer distances. Therefore, its physical properties are suitable for second-messenger signaling (7, 8). Because a proper delivery of oxygen and nutrients to the tissue is essential for the normal function of an organ, in this review we will discuss the roles of superoxide and H2O2 in the physiological and pathophysiological regulation of vasomotor activity of resistance arterioles where blood flow is primarily controlled, with special focus on the coronary microcirculation. The deficiency of endothelium-derived vasodilators such as NO and PGI2 in relation to oxidative stress and the l-arginine consuming enzyme arginase is discussed. © 2013 Kuo and Hein.

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Kuo, L., & Hein, T. W. (2013). Vasomotor regulation of coronary microcirculation by oxidative stress: Role of arginase. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2013.00237

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