Siyuan Zha1, Fei Wang1, Zhen Li1, Zhiyuan Ma2, Ling Yang1, Fang Liu1. 1. a Department of Geriatrics, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China. 2. b The School of Public Economics and Administration, Shanghai University of Finance and Economics , Shanghai , China.
Abstract
Objective: Atherosclerosis involves endothelial injury caused by oxidative stress. Endothelial progenitor cells (EPCs) play important roles in preventing the early stages of atherosclerosis. Meanwhile, poly (ADP-ribose) polymerase 1 (PARP1) utilizes nicotinamide adenine dinucleotide (NAD+) to repair DNA damage. PARP1 overactivation results in excessive NAD+ consumption in the presence of pathological DNA damage. PJ34 is a PARP1 inhibitor that attenuates cellular NAD+ depletion and can prevent endothelial dysfunction. However, few studies have been conducted on its effects on EPCs. In this study, we tried to elucidate the action of PJ34 in rabbit EPCs and tested its effectiveness in rabbit atherosclerosis. Methods: We analyzed the effect of PJ34 supplementation by inducing oxidative damage by H2O2 in vitro and using a rabbit atherosclerosis model induced by a high-fat-diet in vivo. Transwell, immunofluorescence, Matrigel, and western blot analyses, as well as adenoviral vector transfection were used to quantify the levels of reactive oxygen species, proteins, and NAD+. Results: The effects of PJ34 were dependent on SIRT1 levels. In vitro results showed that when oxidative damage attenuated cellular function, PJ34 treatment restored partial functionality. In vivo results confirmed that PJ34 can prevent atherosclerosis in a rabbit model.
Objective: Atherosclerosis involves endothelial injury caused by oxidative stress. Endothelial progenitor cells (EPCs) play important roles in preventing the early stages of atherosclerosis. Meanwhile, poly (ADP-ribose) polymerase 1 (PARP1) utilizes nicotinamide adenine dinucleotide (NAD+) to repair DNA damage. PARP1 overactivation results in excessive NAD+ consumption in the presence of pathological DNA damage. PJ34 is a PARP1 inhibitor that attenuates cellular NAD+ depletion and can prevent endothelial dysfunction. However, few studies have been conducted on its effects on EPCs. In this study, we tried to elucidate the action of PJ34 in rabbit EPCs and tested its effectiveness in rabbit atherosclerosis. Methods: We analyzed the effect of PJ34 supplementation by inducing oxidative damage by H2O2 in vitro and using a rabbit atherosclerosis model induced by a high-fat-diet in vivo. Transwell, immunofluorescence, Matrigel, and western blot analyses, as well as adenoviral vector transfection were used to quantify the levels of reactive oxygen species, proteins, and NAD+. Results: The effects of PJ34 were dependent on SIRT1 levels. In vitro results showed that when oxidative damage attenuated cellular function, PJ34 treatment restored partial functionality. In vivo results confirmed that PJ34 can prevent atherosclerosis in a rabbit model.
Authors: David C Poole; Steven W Copp; Trenton D Colburn; Jesse C Craig; David L Allen; Michael Sturek; Donal S O'Leary; Irving H Zucker; Timothy I Musch Journal: Am J Physiol Heart Circ Physiol Date: 2020-03-20 Impact factor: 4.733