Inhibition of Anaplerosis Attenuated Vascular Proliferation in Pulmonary Arterial Hypertension

Abstract

Vascular remodeling is considered a key event in the pathogenesis of pulmonary arterial hypertension (PAH). However, mechanisms of gaining the proliferative phenotype by pulmonary vascular cells are still unresolved. Due to well-established pyruvate dehydrogenase (PDH) deficiency in PAH pathogenesis, we hypothesized that the activation of another branch of pyruvate metabolism, anaplerosis, via pyruvate carboxylase (PC) could be a key contributor to the metabolic reprogramming of the vasculature. In sugen/hypoxic PAH rats, vascular proliferation was found to be accompanied by increased activation of Akt signaling, which upregulated membrane Glut4 translocation and caused upregulation of hexokinase and pyruvate kinase-2, and an overall increase in the glycolytic flux. Decreased PDH activity and upregulation of PC shuttled more pyruvate to oxaloacetate. This results in the anaplerotic reprogramming of lung vascular cells and their subsequent proliferation. Treatment of sugen/hypoxia rats with the PC inhibitor, phenylacetic acid 20 mg/kg, starting after one week from disease induction, significantly attenuated right ventricular systolic pressure, Fulton index, and pulmonary vascular cell proliferation. PC inhibition reduced the glycolytic shift by attenuating Akt-signaling, glycolysis, and restored mitochondrial pyruvate oxidation. Our findings suggest that targeting PC mediated anaplerosis is a potential therapeutic intervention for the resolution of vascular remodeling in PAH.

Targeting Mitochondrial Metabolic Dysfunction in Pulmonary Hypertension: Toward New Therapeutic Approaches?

“…In addition, the maximization of the ability of the TCA cycle to process the acetyl-CoA produced may be a complementary therapeutic approach that still needs to be explored. The inhibition of the pyruvate carboxylase anaplerosis reaction by phenylacetic acid is a potential therapeutic intervention demonstrated in sugen/hypoxic PAH rats but requires further investigation [107].…”

Endothelial PHD2 deficiency induces apoptosis resistance and inflammation via AKT activation and AIP1 loss independent of HIF2α

“…AKT activation has been found in the vasculopathic pulmonary vessels of hypoxic mice, 58 SuHx rats 59, 60 and patients with IPAH. 29, 59 Deletion of Akt1 58 or pharmacological inhibition of PI3K, an upstream AKT activator, attenuates vascular remodeling and the development of PAH in rodents.…”

Physiopathologie et traitements de l’hypertension artérielle pulmonaire

“…Dans les cellules en train de proliférer, l'activité soutenue du cycle de Krebs nécessite l'apport d'intermédiaires carbonés. L'anaplérose 5 permet de reconstituer les intermédiaires carbonés, par la carboxylation du pyruvate en oxaloacétate par la pyruvate carboxylase, et par la glutaminolyse (désamidation de la glutamine par la glutaminase) [20]. La pyruvate carboxylase joue un rôle majeur dans l'anaplérose et donc dans la régulation de la croissance et de la viabilité des cellules en train de proliférer dont le métabolisme a été modifié, de la phosphorylation oxydante à la glycolyse.…”

“…La pyruvate carboxylase joue un rôle majeur dans l'anaplérose et donc dans la régulation de la croissance et de la viabilité des cellules en train de proliférer dont le métabolisme a été modifié, de la phosphorylation oxydante à la glycolyse. Chez le rat, son inhibition empêche la reprogrammation métabolique des cellules et atténue le remodelage vasculaire pulmonaire dans l'HTP expérimentale [20].…”