Angiotensin II-Mediated Endothelial Dysfunction: Role of Poly(ADP-ribose) Polymerase Activation

Abstract

Angiotensin II (AII) contributes to the pathogenesis of many cardiovascular disorders. Oxidant-mediated activation of poly(adenosine diphosphate-ribose) polymerase (PARP) plays a role in the development of endothelial dysfunction and the pathogenesis of various cardiovascular diseases. We have investigated whether activation of the nuclear enzyme PARP contributes to the development of AII-induced endothelial dysfunction. AII in cultured endothelial cells induced DNA single-strand breakage and dose-dependently activated PARP, which was inhibited by the AII subtype 1 receptor antagonist, losartan; the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin; and the nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester. Infusion of sub-pressor doses of AII to rats for 7 to 14 d induced the development of endothelial dysfunction ex vivo. The PARP inhibitors PJ34 or INO-1001 prevented the development of the endothelial dysfunction and restored normal endothelial function. Similarly, PARP-deficient mice infused with AII for 7 d were found resistant to the AII-induced development of endothelial dysfunction, as opposed to the wild-type controls. In spontaneously hypertensive rats there was marked PARP activation in the aorta, heart, and kidney. The endothelial dysfunction, the cardiovascular alterations and the activation of PARP were prevented by the angiotensin-converting enzyme inhibitor enalapril. We conclude that AII, via AII receptor subtype 1 activation and reactive oxygen and nitrogen species generation, triggers DNA breakage, which activates PARP in the vascular endothelium, leading to the development of endothelial dysfunction in hypertension.

Angiotensin II-induced vascular endothelial dysfunction through RhoA/Rho kinase/p38 mitogen-activated protein kinase/arginase pathway

“…ANG II is an important biologically active component of the renin-angiotensin system and acts through two receptor subtypes, the AT 1 and AT 2 receptors (9). Most of the pathophysiological effects of ANG II, including endothelial dysfunction and processes leading to atherothrombosis, are mediated by the AT 1 receptor subtype (15,38). Given the importance of these pathological processes, we sought to define the signaling pathway by which ANG II enhances arginase activity/expression in endothelial cells and in vascular tissue of ANG II hypertensive mice.…”

Angiotensin II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology

“…Also, endothelial NADPH-oxidase-derived H 2 O 2 induced by AngII was reported to mediate tetrahydrobiopterin deficiency and uncoupling of eNOS [101]. In addition, AngII has been shown to activate PARP [poly(ADP-ribose) polymerase] via the AT 1 receptor through NADPH in ECs [102]. PARP is an energy-consuming enzyme which transfers ADP ribose units to nuclear proteins.…”

Intestinal renin–angiotensin system is stimulated after deletion of Lkb1

“…AngII levels in Lkb1-deficient intestines were increased primarily in the crypt because of altered ACE expression, and this fact compromised survival of the proliferative crypt cells. AngII treatment is known to be proapoptotic, and it involves reactive oxygen species generation 63 64. The precise role of Lkb1 in the apoptotic response and the possible involvement of AngII and reactive oxygen species are yet to be elucidated.…”