Inhibiting pyruvate kinase muscle isoform 2 regresses group 2 pulmonary hypertension induced by supra-coronary aortic banding

Xiong, Ping Yu and Motamed, Mehras and Chen, Kuang-Hueih and Dasgupta, Asish and Potus, François and Tian, Lian and Martin, Ashley and Mewburn, Jeffrey and Jones, Oliver and Thébaud, Arthur and Archer, Stephen L. (2022) Inhibiting pyruvate kinase muscle isoform 2 regresses group 2 pulmonary hypertension induced by supra-coronary aortic banding. Acta Physiologica, 234 (2). e13764. ISSN 1748-1708 (https://doi.org/10.1111/apha.13764)

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Abstract

Introduction: Group 2 pulmonary hypertension (PH) has no approved PH-targeted therapy. Metabolic remodelling, specifically a biventricular increase in pyruvate kinase muscle (PKM) isozyme 2 to 1 ratio, occurs in rats with group 2 PH induced by supra-coronary aortic banding (SAB). We hypothesize that increased PKM2/PKM1 is maladaptive and inhibiting PKM2 would improve right ventricular (RV) function. Methods: Male, Sprague-Dawley SAB rats were confirmed to have PH by echocardiography and then randomized to treatment with a PKM2 inhibitor (intraperitoneal shikonin, 2 mg/kg/day) versus 5% DMSO (n = 5/group) or small interfering RNA-targeting PKM2 (siPKM2) versus siRNA controls (n = 7/group) by airway nebulization. Results: Shikonin-treated SAB rats had milder PH (PAAT 32.1 ± 1.3 vs 22.1 ± 1.2 ms, P =.0009) and lower RV systolic pressure (RVSP) (31.5 ± 0.9 vs 55.7 ± 1.9 mm Hg, P <.0001) versus DMSO-SAB rats. siPKM2 nebulization reduced PKM2 expression in the RV, increased PAAT (31.7 ± 0.7 vs 28.0 ± 1.3 ms, P =.025), lowered RVSP (30.6 ± 2.6 vs 42.0 ± 4.0 mm Hg, P =.032) and reduced diastolic RVFW thickness (0.69 ± 0.04 vs 0.85 ± 0.06 mm, P =.046). Both shikonin and siPKM2 regressed PH-induced medial hypertrophy of small pulmonary arteries. Conclusion: Increases in PKM2/PKM1 in the RV contribute to RV dysfunction in group 2 PH. Chemical or molecular inhibition of PKM2 restores the normal PKM2/PKM1 ratio, reduces PH, RVSP and RVH and regresses adverse PA remodelling. PKM2 merits consideration as a therapeutic cardiac target for group 2 PH.

ORCID iDs

Xiong, Ping Yu, Motamed, Mehras, Chen, Kuang-Hueih, Dasgupta, Asish, Potus, François, Tian, Lian ORCID logoORCID: https://orcid.org/0000-0002-9699-8009, Martin, Ashley, Mewburn, Jeffrey, Jones, Oliver, Thébaud, Arthur and Archer, Stephen L.;