PARP1-PKM2 Axis Mediates Right Ventricular Failure Associated With Pulmonary Arterial Hypertension

Tsukasa Shimauchi; Olivier Boucherat; Tetsuro Yokokawa; Yann Grobs; WenHui Wu; Mark Orcholski; Sandra Martineau; Junichi Omura; Eve Tremblay; Kana Shimauchi; Valérie Nadeau; Sandra Breuils-Bonnet; Roxane Paulin; François Potus; Steeve Provencher; Sébastien Bonnet

doi:10.1016/j.jacbts.2022.01.005

PARP1-PKM2 Axis Mediates Right Ventricular Failure Associated With Pulmonary Arterial Hypertension

JACC Basic Transl Sci. 2022 Mar 16;7(4):384-403. doi: 10.1016/j.jacbts.2022.01.005. eCollection 2022 Apr.

Authors

Tsukasa Shimauchi¹, Olivier Boucherat^{1

2}, Tetsuro Yokokawa¹, Yann Grobs¹, WenHui Wu¹, Mark Orcholski¹, Sandra Martineau¹, Junichi Omura¹, Eve Tremblay¹, Kana Shimauchi¹, Valérie Nadeau¹, Sandra Breuils-Bonnet¹, Roxane Paulin^{1

2}, François Potus^{1

2}, Steeve Provencher^{1

2}, Sébastien Bonnet^{1

2}

Affiliations

¹ Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada.
² Department of Medicine, Université Laval, Québec, Québec, Canada.

Abstract

The authors show that increased poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) and pyruvate kinase muscle isozyme 2 (PKM2) expression is a common feature of a decompensated right ventricle in patients with pulmonary arterial hypertension and animal models. The authors find in vitro that overactivated PARP1 promotes cardiomyocyte dysfunction by favoring PKM2 expression and nuclear function, glycolytic gene expression, activation of nuclear factor κB-dependent proinflammatory factors. Pharmacologic and genetic inhibition of PARP1 or enforced tetramerization of PKM2 attenuates maladaptive remodeling improving right ventricular (RV) function in multiple rodent models. Taken together, these data implicate the PARP1/PKM2 axis as a critical driver of maladaptive RV remodeling and a new promising target to directly sustain RV function in patients with pulmonary arterial hypertension.

Keywords: CM, cardiomyocyte; CO, cardiac output; ET, endothelin; NF-κB, nuclear factor κB; PAB, pulmonary artery banding; PAH, pulmonary arterial hypertension; PARP1; PARP1, poly(adenosine diphosphate–ribose) polymerase 1; PKM2; PKM2, pyruvate kinase muscle isozyme 2; RV, right ventricular; STAT3, signal transducer activator of transcription 3; WT, wild-type; cKO, conditional knockout; pulmonary hypertension; right ventricle.