The Mechanism Of Poly (ADP-ribose) Polymerase 1 Regulate The Transcription Of Genes Correlated With Cardiovascular System

Accumulating evidence suggests that the reactive nitrogen and oxygen species are generated in vascular smooth muscle celsl, vascular endothelial cells, cardiomyocytes, cardiac fibroblasts during myocardial ischemia/reperfusioninjury, various forms of heart failure or cardiomyopathies, circulatory shock, cardiovascular aging, diabetic complications, myocardial hypertrophy, atherosclerosis, and vascularremodeling following injury. These reactive species induce oxidative DNA damage and consequent activation of the nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP1),the most abundant isoform of the PARP enzyme family. PARP1 overactivation, on the one hand, depletes its substrate, NAD+, slowing the rate of glycolysis, electron transport, and ATP formation, eventually leading to the functional impairment or death of the endothelial cells and cardiomyocytes. On the other hand, PARP1 activation modulates important inflammatory pathways, and PARP1 activity can also be modulated by several endogenous factorssuch as various kinases, purines, vitamin D, thyroid hormones, polyamines, and estrogens,just to mention a few. Recent studies have demonstrated that pharmacological inhibition of PARP1 provides significant benefits in animal models of cardiovascular disorders, and novel PARP1 inhibitors have entered clinical development for various cardiovascular indications. Because PARP1 inhibitors can enhance the effect of anticancer drugs and decrease angiogenesis, their therapeutic potential is also being explored for cancer treatment. This review discusses the therapeutic effects of PARP1 inhibitors in myocardial ischemia/reperfusion injury, various forms of heart failure, cardiomyopathies,circulatory shock, cardiovascular aging, diabetic cardiovascular complications, myocardial hypertrophy, atherosclerosis, vascular remodeling following injury, angiogenesis, and also summarizes our knowledge obtained from the use of PARP1 knockout mice in the various preclinical models of cardiovascular diseases.In this study, partⅠexplored the relationship of PARP1 and ERαin cultured rat vascular smooth muscle cell, and revealed the mechanism that PARP1 regulated the activity of ERa binding to ERE; partⅡobservated the role of PARP1 in the fibrosis of rat aorta which induced by hypertension. Aims:Estradiol contributes importantly to the protective effect to post-menopause women through estrogen receptorα(ERα) in rat vascular smooth muscle cell. This study aims to explore the mechanism how PARP1 regulate ERαin rat vascular smooth muscle cell.Methods and results:In this study, we demonstrated that ERαwas poly(ADP-ribosyl)ated in cultured rat vascular smooth muscle cell. EMSA and Southwestern blot assays showed that incubation of nuclear extracts from vascular smooth muscle cell with active DNA and NAD+ increased the DNA binding activities of ERa (P<0.05); incubation of recombinant ERαprotein with NAD+,active DNA and PARP1 increased the DNA binding activities of ERα(P<0.01). Treatment with estradiol alone activated PARP1 and enhanced poly (ADP-ribosyl)ation of ERα(P<0.05). Estradiol also increased the basal DNA binding activities of ERαand ERE (P<0.05) in cultured cells. The nuclear translocation of ERαwas effectively promoted when PARP1 inhibited by 3AB, PJ34 or siRNA, meaningwhile,both the DNA binding of ERαand ERE and ERα-driven transcription(including cyclinD,IGF,TGF alpha) increased.Conclusions:This study illustrated that ERαwas poly(ADP-ribosyl)ated by PARP1, in a cell free system, poly(ADP-ribosyl)ation enhanced the DNA binding of ERαto ERE. estradiol promoted poly(ADP-ribosyl)ation of ERαthrough activation of PARP1, enhanced the DNA binding of ERαto ERE. In the other hand, the activity of PARP1 would inhibited the nuclear translocation of ERα, and decreased the ERα-driven transcription in c rat vascular smooth muscle cell. Aims:With the development of hypertension, fibrosis of the organs such as heart, aorta, liver, kidney, spleen is a important physiopathological progress. This study aims to explore the role of PARP1 in rat aorta fibrosis induced by hypertension.Methods and results:In this study, AngⅡinfusion promoted PARP1 activation in the aorta of rats. Rrats was infused AngⅡsubcutaneously via osmotic pumps, and from the2nd day to the 14th day, the SBP of rats was elevated remarkably (from 105±0.733 mmHg to 126.77±1.42 mmHg), Treatment with 3AB and PJ34 decreased the SBP by 20% and 12% on the 14th day in the AngⅡinfused rats, respectively. Furthermore,3AB treatment decreased SBP of non-Ang II-infused rats by 5.1% on the 14th day of treatment; Masson-trichrome staining revealed that AngⅡinfusion increased the percentage area of collagen within the thoracic aorta from 9.69±1.91% to 19.6±2.54%; and treatment with 3AB or PJ34 decreased the percentage area of collagen to 7.53±2.06% or 6.34±2.54% on the 14th day of Ang II infusion. Western blot and realtime RT-PCR assays showed that Ang II infusion promoted the expression of CoⅠα1、CoⅢα1、TIMP1、MMP9 in aorta. Treatment with 3AB or PJ34 reversed the effect.Conclusions:In the progress of fibrosis of rat aorta induced by hypertension, PARP1 play a important role in regulating genes CoⅠα1、CoⅢα1、TIMP1、MMP9 which related with fibrosis.