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

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.

Automated summary

Inhibition of PKM2 can improve right ventricular function in rats with group 2 pulmonary hypertension, reducing the severity of PH and lowering RV systolic pressure. PKM2 inhibition may be a potential therapeutic target for group 2 PH.