Role of carbonic anhydrases 9 and 12 in hypoxia and non-hypoxia induced pulmonary hypertension

Abstract

Pulmonary hypertension (PH) is a severe and incurable disease characterized by a progressive elevation of pulmonary arterial pressure, ultimately resulting in right ventricle failure and death. Pulmonary vascular remodeling is a crucial event in the disease development and its portrayed by several cancer-like features, such as increased proliferation, migration and resistance to apoptosis of pulmonary vascular cells. Additionally, a metabolic shift from oxidative phosphorylation to glycolysis, a hallmark of malignant cell transformation, has been described in pulmonary vascular cells. Carbonic anhydrases (CAs), especially CA9 and 12, have become intriguing topics in cancer research due to their overexpression in various tumors and limited expression in normal tissues. Elevated CA9 plasma levels are described in various cancers and often associated with disease progression. They play a crucial role in cancer cells' intracellular pH regulation, hyperproliferative phenotype, and various functional aspects, such as adhesion, migration, invasion and metastasis. Despite significant progress in pulmonary hypertension therapy, new treatment strategies are needed. Metabolic-modulating therapies targeting glycolysis could be effective against proliferative cells in the pulmonary artery wall. Our study aimed to investigate the role of CA9 and 12 in hypoxia and non-hypoxia induced PH. We have successfully demonstrated an elevated CA9 and 12 expression profile in idiopathic pulmonary arterial hypertension (IPAH) patients, in vivo and in vitro models of hypoxia and non-hypoxia induced PH, driven by the HIF-1α transcription factor. This study strongly indicates the important role of CA9 and 12 in hypoxia and non-hypoxia induced proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Furthermore, CA9 and 12 are involved in PASMCs intracellular pH homeostasis and acidification of their extracellular milieu, subsequently activating numerous protein kinases upon hypoxia exposure. Additionally, this study demonstrated the beneficial therapeutic effect of CA9 and 12 pharmacological inhibition in two experimental models of PH, the monocrotaline model in rats and the chronic hypoxia model in mice. Finally, this study revealed an increase in circulating CA9 levels in PH patients with uncoupled right ventricle-arterial coupling compared to the coupled group. In conclusion, CA9 and 12 play an important role in hypoxia and non-hypoxia induced PH by contributing to the pulmonary vascular remodeling and may represent novel therapeutic targets for the treatment of pulmonary hypertension in the future.