Pleiotropic Effects of Pyruvate Kinase M2 in Right Ventricular Failure and Pulmonary Arterial Hypertension

Corresponding Author

Pulmonary arterial hypertension (PAH) is an expanding public health problem world-wide and is associated with significant morbidity, mortality, and health care–related costs.¹ The primary pathophysiology involves pulmonary vasoconstriction and structural remodeling with resulting increased pulmonary vascular resistance. This leads to progressive hypertrophy of the right ventricle (RV) with subsequent failure that is ultimately fatal. As the leading cause of death in PAH, RV failure is a critical component of the disease that is indirectly and inadequately targeted by current therapies that predominantly aim to dilate the pulmonary arterial circulation.² To improve PAH clinical outcomes, new anti-remodeling interventions are being evaluated, but their direct effects on the RV are unknown. In addition, there is an urgent need to better understand the mechanisms underlying RV failure in PAH in order to pursue therapeutic targeting and improve survival.

In this issue of JACC: Basic to Translational Science, Shimauci et al³ provide compelling evidence that the PARP1-PKM2 axis mediates RV failure in experimental pulmonary hypertension. Pyruvate kinase muscle isozyme 2 (PKM2) is a metabolic enzyme that has a dual function as a transcriptional coactivator when it translocates to the nucleus. Nuclear localization is facilitated by dimerization, a process regulated by poly(ADP-ribose) polymerase 1 (PARP1) and leads to up-regulation of glycolytic, inflammatory and profibrotic genes through transcriptional coactivation of hypoxia-inducible factor 1a, nuclear factor κB, and signal transducer and activator of transcription 3. The PARP1-PKM2 pathway is known to contribute to pulmonary vascular remodeling in experimental PAH, but the present study showed that PARP1 and PKM2 expression is also up-regulated in decompensated RV from PAH patients and nonhuman animal models. Pharmacologic, molecular and genetic in vitro and in vivo approaches are presented to support a causal relationship between the activation of the PARP1-PKM2 axis in cardiomyocytes and RV failure, and the findings are corroborated by descriptive studies in human biospecimens that lend support to the translational relevance of the project. Importantly, the pharmacologic inhibitor of PARP1 olaparib is currently being evaluated as an anti-remodeling intervention in a clinical trial for PAH (Olaparib for PAH: A Multicenter Clinical Trial [OPTION]; NCT03782818); it is therefore very exciting to recognize that it has additional direct cardioprotective effects that will likely enhance its therapeutic efficacy. Although this remains to be determined in the ongoing clinical trial, the present study highlights the therapeutic potential of interventions with pleiotropic effects.

Oxidant stress, inflammation, and metabolic dysregulation are causally related to cardiomyocyte energy failure and fibrosis in the decompensated RV; therefore, Shimauchi et al³ focused their studies predominantly on cardiomyocytes, but their findings also support involvement of the PARP1-PKM2 axis in cardiac fibroblast homeostasis, and that needs to be further delineated in future studies. Beyond the newly described role of PKM2 in cardiac cellular homeostasis, it is known that PKM2 has direct effects on vascular and immune cells so there are likely far reaching favorable effects of interventions that globally target PKM2 in PAH where inflammation and disrupted vascular homeostasis are key contributors. From the translational perspective, it is important to point out that none of the in vivo experiments in the present study addressed whether inhibition or genetic ablation of the PARP1-PKM2 axis is effective in reversing established maladaptive RV remodeling. The in vivo interventions (pharmacologic inhibition of PARP1 with the use of olaparib or enforced tetramerization of PKM2 with the use of TEPP-46) were initiated after adaptive RV remodeling was confirmed (3 weeks after pulmonary artery [PA] banding surgery) but before the development of maladaptive RV remodeling. Similarly, both the global and the cardiomyocyte-specific gene ablation approaches in the PA banding and Sugen/hypoxia models resulted in a “prevention strategy” without the opportunity to address reversibility of RV remodeling. These questions can be addressed with pharmacologic “reversal strategies” and/or conditional gene ablation approaches in future studies.

The links between metabolism and transcriptional regulation are increasingly appreciated and involve complex interactions between metabolic enzymes and intermediates, metabolism-related transcription factors, and epigenetic modifications.⁴ Translocation of metabolic enzymes to the nucleus such as ATP citrate lyase, pyruvate dehydrogenase complex, glycogen synthase kinase 3β, pyruvate kinase, and others has previously been described primarily in immune and cancer cells.^5,6 More commonly, transcriptional coactivation by metabolic enzymes is dependent on enzymatic activity whereby a transcription factor is phosphorylated or histones are otherwise modified resulting in altered binding. As described in the present study, nuclear translocation of PKM2 also occurs in cardiomyocytes where the activity of PKM2 as a transcriptional coactivator appears to be at least partially independent from its enzymatic activity. It is exciting to consider the therapeutic implications of approaches that leverage this knowledge in other forms of heart failure. The dual function of PKM2 as a metabolic enzyme and a transcriptional regulator in cardiomyocytes opens new opportunities for therapeutic targeting in heart disease. Specifically in PAH therapeutics, the pleiotropic effects of PKM2 targeting the RV and the pulmonary vasculature make it a promising new anti-remodeling and cardioprotective approach that remains to be tested in clinical trials.

Funding Support and Author Disclosures

The author has reported that she has no relationships relevant to the contents of this paper to disclose.