TRPC6, a therapeutic target for pulmonary hypertension

Abstract

Idiopathic pulmonary arterial hypertension (PAH) is a fatal and progressive disease. Pulmonary vasoconstriction due to pulmonary arterial smooth muscle cell (PASMC) contraction and pulmonary arterial remodeling due to PASMC proliferation are causes for increased pulmonary vascular resistance in patients with PAH. We and others observed upregulation of TRPC6 channels in PASMC from patients with PAH. An increase in cytosolic Ca2+ concentration ([Ca2+]cyt) in PASMC triggers PASMC contraction and vasoconstriction, while Ca2+-dependent activation of PI3K/AKT/mTOR pathway is pivotal for cell proliferation and gene expression. Despite evidence supporting a pathological role of TRPC6, no selective and orally bioavailable TRPC6 blocker has yet been developed and tested for treatment of PAH. We sought to investigate whether block of receptor-operated Ca2+ channels or TRPC6 can reverse established PH in mice via inhibiting Ca2+-dependent activation of AKT/mTOR signaling. Here we report that intrapulmonary application of 2-aminoethyl diphenyl borniate (2-APB), a non-selective blocker of cation channels or BI-749237, a selective blocker of TRPC6, significantly and reversibly inhibited acute hypoxic pulmonary vasoconstriction. Intraperitoneal injection of 2-APB significantly attenuated the development of PH and partially reversed established PH. Oral gavage of the selective TRPC6 blocker BI-749237 reversed established PH by 50% via regression of pulmonary vascular remodeling. Furthermore, 2-APB and BI-749237 both inhibited PDGF- and serum-mediated phosphorylation of AKT and mTOR in PASMC. These results indicates that the receptor-operated and mechanosensitive TRPC6 channel is a good target for developing novel treatment for PAH. BI-749237, a selective TRPC6 blocker, is potentially a novel and effective drug for treating PAH.

Role of Store-Operated Ca2+ Entry in the Pulmonary Vascular Remodeling Occurring in Pulmonary Arterial Hypertension

“…Recently, Jain et al demonstrated that oral gavage with TRPC6 blocker BI-749237 reduced the development of PH induced by CH exposure in mice [ 191 ], suggesting that TRPC6 could be a potential target in PAH.…”

Crucial Role of Stromal Interaction Molecule-Activated TRPC-ORAI Channels in Vascular Remodeling and Pulmonary Hypertension Induced by Intermittent Hypoxia

“…In this study, 2-APB was administered with osmotic pumps at a delivery rate of 10 mg/kg per day, which is similar to the daily dose range used by Smith et al (2015) , Castillo-Galán et al (2016 , 2022) and Jain et al (2021) to block STOC in vivo . Indeed, Smith et al (2015) treated chronic hypoxic mice with 2-APB (1 mg/kg/day i.p.)…”

“… Castillo-Galán et al (2016 , 2022) , administered 2-APB (10 mg/kg/day i.v.) to neonatal lambs with a partial or full gestation in high altitude to ameliorate the pulmonary hypertension and vascular remodeling, and Jain et al (2021) administrated 2-APB (1 mg/kg per day i.p.) to attenuate pulmonary hypertension in hypoxic mice.…”

“…Recently, we found that CIH produced the upregulation of mRNA and protein levels of TRPC1, TRPC4, TRPC6, ORAI1, and STIM1 subunits in the rat lung tissue, which paralleled the vascular remodeling and pulmonary hypertension ( Castillo-Galán et al, 2020 ), suggesting that STOC participate in the vascular alterations induced by CIH. Accordingly, to assess the contribution of STOC on the CIH-induced pulmonary vascular alterations, we study the effects of the STOC non-selective inhibitor 2-aminoethyldiphenylborinate (2-APB) ( Bootman et al, 2002 ; Smith et al, 2015 ; Castillo-Galán et al, 2016 , 2022 ; Jain et al, 2021 ) on the development of pulmonary hypertension and vascular remodeling induced by CIH in a well stablished preclinical model of OSA ( Del Rio et al, 2010 , 2012 , 2014 ; Iturriaga et al, 2014 , Iturriaga and Castillo-Galán, 2019 ). We also determined the effects of 2-APB on systemic and lung oxidative stress induced by CIH, because 2-APB ameliorates the oxidative stress in a heart ischemia-reperfusion model in mice ( Morihara et al, 2017 ) and rat ( Shen et al, 2021 ).…”

A Pharmacokinetic and Metabolism Study of the TRPC6 Inhibitor SH045 in Mice by LC-MS/MS

“…In lung, another current subject in search for treatment options, increased TRPC6 responses of smooth muscle and vascular endothelial cells are associated with acute hypoxic vasoconstriction [ 13 ] but also with idiopathic pulmonary arterial hypertension (IPAH) [ 14 ] and lung ischemia-reperfusion edema (LIRE) [ 15 , 16 ].…”