Inhibition of transient receptor potential channel 6 (TRPC6) may be a novel therapeutic approach for treating pulmonary arterial hypertension (PAH), according to a new study published in the American Journal of Physiology – Lung Cellular and Molecular Physiology.
The results showed that the administration of BI-749327, a selective blocker of TRCP6, resulted in roughly 50% reversal of pulmonary hypertension in a mouse model of PAH.
BI-749327 treatment inhibited hypoxia-induced increases in right ventricular systolic pressure (RVSP) by 47.2%, mean pulmonary arterial pressure by 47.4%, and right ventricular contractility by 53.3%. Administration of 2-aminoethyl diphenylborinate (2-APB), a nonselective cation blocker, also led to similar reductions in RVSP (47.3%) and right ventricular contractility (50.2%).
Study results also showed that administration of BI-749327 or 2-APB inhibited the growth factor-mediated phosphorylation of protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in pulmonary arterial smooth muscle cells (PASMCs). The AKT/mTOR signaling pathway is generally associated with the proliferation of PASMCs.
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Treatment with either inhibitor also resulted in regressed lung vascular remodeling by 60% to 75% with 2-APB and 70% to 75% with BI-749327.
“These data indicate that nonselective inhibition of TRPC channels with 2-APB and selective inhibition of TRPC6 channels with BI-749327 are both sufficient to ameliorate established PH via inhibition of pulmonary vasoconstriction and regression of pulmonary vascular remodeling,” the authors said.
“More clinical studies in patients with PH are needed to define the therapeutic potential of inhibition of TRPC6 channels or BI-749327 (a selective TRPC6 antagonist) on different subgroups of PH.”
During the study, 8-week old male mice were used for the measurement of pulmonary hemodynamics, lung vascular reactivity, and the detection of pulmonary vascular remodeling. To induce pulmonary hypertension, a group of mice was placed in a hypoxic (10% O2) but normobaric chamber for 4 weeks.
Control mice were placed in a normoxic environment (21% O2). Normal human PASMCs and HEK-293 cells were also used for cell assays during the study.
Jain PP, Lai N, Xiong M, et al. TRPC6, a therapeutic target for pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2021;321(6):L1161-L1182. doi:10.1152/ajplung.00159.2021