1. Academic Validation
  2. TRPC6, a therapeutic target for pulmonary hypertension

TRPC6, a therapeutic target for pulmonary hypertension

  • Am J Physiol Lung Cell Mol Physiol. 2021 Dec 1;321(6):L1161-L1182. doi: 10.1152/ajplung.00159.2021.
Pritesh P Jain 1 2 Ning Lai 1 3 Mingmei Xiong 1 3 Jiyuan Chen 1 3 Aleksandra Babicheva 1 2 Tengteng Zhao 1 2 Sophia Parmisano 1 Manjia Zhao 1 Cole Paquin 1 Moreen Matti 1 Ryan Powers 1 Angela Balistrieri 1 2 Nick H Kim 2 Daniela Valdez-Jasso 4 Patricia A Thistlethwaite 5 John Y-J Shyy 6 Jian Wang 1 3 Joe G N Garcia 7 Ayako Makino 8 Jason X-J Yuan 1 2
Affiliations

Affiliations

  • 1 Section of Physiology, University of California, San Diego, La Jolla, California.
  • 2 Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California.
  • 3 State Key Laboratory of Respiratory Medicine and First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • 4 Department of Bioengineering, University of California, San Diego, La Jolla, California.
  • 5 Division of Cardiothoracic Surgery, Department of Surgery, University of California, San Diego, La Jolla, California.
  • 6 Division of Cardiovascular Medicine, University of California, San Diego, La Jolla, California.
  • 7 Department of Medicine, The University of Arizona, Tucson, Arizona.
  • 8 Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California.
Abstract

Idiopathic pulmonary arterial hypertension (PAH) is a fatal and progressive disease. Sustained vasoconstriction due to pulmonary arterial smooth muscle cell (PASMC) contraction and concentric arterial remodeling due partially to PASMC proliferation are the major causes for increased pulmonary vascular resistance and increased pulmonary arterial pressure in patients with precapillary pulmonary hypertension (PH) including PAH and PH due to respiratory diseases or hypoxemia. We and Others observed upregulation of TRPC6 channels in PASMCs from patients with PAH. A rise in cytosolic CA2+ concentration ([CA2+]cyt) in PASMC triggers PASMC contraction and vasoconstriction, while CA2+-dependent activation of PI3K/Akt/mTOR pathway is a pivotal signaling cascade for cell proliferation and gene expression. Despite evidence supporting a pathological role of TRPC6, no selective and orally bioavailable TRPC6 antagonist has yet been developed and tested for treatment of PAH or PH. In this study, we sought to investigate whether block of receptor-operated CA2+ channels using a nonselective blocker of cation channels, 2-aminoethyl diphenylborinate (2-APB, administered intraperitoneally) and a selective blocker of TRPC6, BI-749327 (administered orally) can reverse established PH in mice. The results from the study show that intrapulmonary application of 2-APB (40 µM) or BI-749327 (3-10 µM) significantly and reversibly inhibited acute alveolar hypoxia-induced pulmonary vasoconstriction. Intraperitoneal injection of 2-APB (1 mg/kg per day) significantly attenuated the development of PH and partially reversed established PH in mice. Oral gavage of BI-749327 (30 mg/kg, every day, for 2 wk) reversed established PH by ∼50% via regression of pulmonary vascular remodeling. Furthermore, 2-APB and BI-749327 both significantly inhibited PDGF- and serum-mediated phosphorylation of Akt and mTOR in PASMC. In summary, the receptor-operated and mechanosensitive TRPC6 channel is a good target for developing novel treatment for PAH/PH. BI-749327, a selective TRPC6 blocker, is potentially a novel and effective drug for treating PAH and PH due to respiratory diseases or hypoxemia.

Keywords

BI-749327; calcium signaling; hypoxic pulmonary vasoconstriction; pulmonary hypertension; transient receptor potential channel.

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