15 February 2020 by Tsukasa Shimauchi

Role of PARP1-PKM2/inflammation/oxidative DNA damage axis in the pathogenesis of right ventricular failure associated with pulmonary arterial hypertension

Background: Right ventricular failure (RVF) is an independent poor prognostic factor for pulmonary arterial hypertension (PAH) patients. Studies have revealed a metabolic shift from oxidative phosphorylation to glycolysis (Warburg effect) in compensated RV hypertrophy (cRVH). Nuclear pyruvate kinase muscle isozyme M2 (PKM2) promotes Warburg effect and PKM2/PKM1 ratio is established as a marker of glycolysis. Although the DNA damage response protein Poly ADP-ribose polymerase 1 (PARP1) was documented to induce PKM2 nuclear translocation and enhances Warburg effect in cancer, their role in RVF has never been studied. We hypothesized sustained PARP1 activation accounts for nuclear PKM2 localization, contributing to cardiomyocyte dysfunction and thus decompensated RV hypertrophy (dRVH).

Methods and Results: We found by Western blot (WB) that PKM2/PKM1 ratio was upregulated in cRVH (Cardiac index >2.2, n=14) and dRVH patients (died with RVF, n=9), compared to control donors (n=14), and correlated with RV hypertrophy and fibrosis. Similar findings were found in three PH rat models (monocrotaline, pulmonary artery banding and Sugen-hypoxia). Interestingly, cardiac inflammation (NF-kappaB, IL-8, CD68), oxidative DNA damage (PARP1, MTH1, 8-oxodG), and apoptosis (TUNEL) were significantly increased in dRVH compared to cRVH despite similar PKM2/PKM1 ratios. Specifically, PARP1 expression inversely correlated with cardiac output and positively correlated with ANP, RV hypertrophy and fibrosis; suggesting that persistent DNA damage repair by PARP1 promotes dRVH. Using neonatal rat RV cardiomyocytes, we confirmed DNA damage promotes nuclear expression of PARP1 and PKM2, leading to inflammation (NF-kappaB), oxidative DNA damage (8-OxoDG) and apoptosis (TUNEL). PARP1 inhibitor (ABT888) prevents nuclear retention of PKM2 and suppresses cardiomyocyte dysfunction (inflammation, oxidative DNA damage, apoptosis). (All p<0.05)

Conclusions: We demonstrated for the first time that PARP1-PKM2/inflammation/oxidative DNA damage axis is implicated in the transition from cRVH to dRVH and suppression of PKM2 nuclear function by PARP1 inhibitor may represent a new strategy to improve RV function.
(300/300 words)

About the author


profile picture of Tsukasa Shimauchi

Tsukasa Shimauchi

MD, PhD

Pulmonary Hypertension and Vascular Biology Research Group of Quebec Heart and Lung Institute, Laval University

Canada

Topics

Inflammatory and Immune Cells
Pulmonary Hypertension
Right Heart Failure

Key Contributors

Tsukasa Shimauchi, Junichi Omura, Sandra Breuils-Bonnet, Valerie Nadeau, Roxane Paulin, Steeve Provencher, Olivier Boucherat, S├ębastien Bonnet Pulmonary Hypertension and Vascular Biology Research Group of Quebec Heart and Lung Institute, Laval University, Quebec, Canada


Comments (0)

Our research platform is the world.

Through worldwide collaboration, we can begin to answer the question of a global disease.

Join the PVRI
standard-example-image.jpg