Arginase and the Aging Cardiovascular System

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DESCRIPTION (provided by applicant): Abnormal endothelial NO vasodilator mechanisms contribute to increased cardiovascular risk in the aging cardiovascular system. L-arginine, the NO synthase substrate, improves endothelial dependent vasodilatation by unknown mechanism(s), since intracellular concentrations of L-arginine far exceed the Kd for nitric oxide synthase (NOS). The observation that L-arginine administration increases NO synthesis and enhances endothelial function even in the setting of apparently adequate L-arginine levels in the cell has come to be called the "L-arginine paradox". Arginase, an enzyme of the urea cycle also uses L-arginine as a substrate and is present in cardiovascular tissue. Our preliminary data demonstrate that the L-arginine metabolizing enzyme, arginase, reciprocally regulates vascular endothelial NOS activity, and directly influences vascular relaxation in rats. Furthermore, arginase activity and expression are increased in agingrat vessels, and arginase inhibition attenuates the increased reactive oxygen species (ROS) produced in old rat vascular tissue. We hypothesize that: 1) endothelial arginase limits endothelial NO production and thus, endothelial-dependent vasodilatation, by competing for intracellular L-arginine; 2) vascular endothelial dysfunction of aging is associated with increased expression of endothelial arginase, and inhibition of arginase restores NO-dependent signaling and endothelial function to that of the young phenotype; 3) relative substrate (L-arginine) deficiency enhances ROS production further compromising endothelial function by altering the balance between NO and 02-; and 4) chronic arginase inhibition will restore Larginine reponsiveness, enhance NO signaling, and decrease ROS production thereby restoring altered integrated cardiovascular parameters (increased vascular and ventricular stiffness and altered ventriculararterial coupling) to that of the young phenotype. We will study the regulatory role of arginase in normal endothelial function and NO signaling, as well as its role in the pathophysiology of endothelial dysfunction associated with aging. These experiments will offer novel insights into regulation of the NO signaling pathway, and the balance between NO and 02- in endothelial function, with important therapeutic implications for a wide variety of disorders characterized by endothelial dysfunction.