Poly(ADP‐ribose)polymerase 1 inhibition protects against age‐dependent endothelial dysfunction

Abstract

Age-related endothelial dysfunction is closely associated with the local production of reactive oxygen species (ROS) within and in the vicinity of the vascular endothelium. Oxidant-induced DNA damage can activate the nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1), leading to endothelial dysfunction in various pathophysiological conditions. The present study aimed to investigate the role of PARP-1 in age-dependent changes in endothelial cell function and its underlying mechanism. Wild-type (WT) and PARP-1(-/-) mice were divided into young (2 months) and old (12 months) groups. Isolated aortic rings were suspended to record isometric tension to assess endothelial function. Nitric oxide (NO) production and content in plasma were detected by spectrophotometry. Superoxide (O2(-) production was detected by dihydroethidium. Expression of PARP-1, endothelial nitric oxide synthase (eNOS), induced nitric oxide synthase (iNOS), and arginase-2 (Arg2) was assessed by western blot analysis. Endothelium-dependent relaxation in response to acetylcholine was lost in old WT, but not PARP-1(-/-), mice. Endothelium-independent vasodilation was not impaired in aging mice. Production of O2(-) was greater in aging WT mice than young or aging PARP-1(-/-) mice. eNOS expression was not affected by aging in WT or PARP-1(-/-) mice, but p-eNOS expression decreased and iNOS and Arg2 levels were upregulated only in aging WT mice. In conclusion, PARP-1 inhibition may protect against age-dependent endothelial dysfunction, potentially by regulating NO bioavailability via iNOS. Inhibition of PARP-1 may help in vascular aging prevention.

Role of PARP and TRPM2 in VEGF Inhibitor‐Induced Vascular Dysfunction

“… 16 In the present study, we showed that axitinib decreases NO signaling in human endothelial cells, effects that are reversed by olaparib. This is further corroborated by others showing that PARP inhibition improves hyperhomocysteinemia‐ 30 and age‐dependent endothelial dysfunction 31 by regulating NO bioavailability. PARP‐1 inhibition was also shown to improve endothelial function by enhancing VEGFR2/Akt/BAD phosphorylation, and by reducing inflammation via NF‐κB.…”

MicroRNAs Modulate Oxidative Stress in Hypertension through PARP‐1 Regulation

“…Many other cellular processes also rely on PARP-1 signaling, and abnormal PARP-1 activity has been attributed to various age-related diseases, including hypertension [23–25]. Consistent with these findings, inhibiting PARP-1 activity in endothelial cells protects against endothelial dysfunction [26, 27] and PARP-1 inhibitors are under consideration as a treatment for pulmonary hypertension [28]. However, differential expression of PARP-1 has not been investigated with respect to health disparities in essential hypertension.…”

The Good, the Bad, and the Ugly of ROS: New Insights on Aging and Aging‐Related Diseases from Eukaryotic and Prokaryotic Model Organisms

“…For instance, in aging rats, treatment with the PARP inhibitor INO-1001 reduces cardiovascular disorders [ 126 ], and treatment with the PARP inhibitor PJ34 improves myocardial contractile function and restores endothelial function [ 127 ]. Furthermore, PARP-1 inhibition may protect against age-dependent endothelial dysfunction, potentially by regulating NO bioavailability via iNOS [ 128 ].…”