TRPC6, a therapeutic target for pulmonary hypertension

Area of Science:

• Cardiovascular Research
• Pulmonary Medicine
• Molecular Pharmacology

Background:

• Idiopathic pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary vascular resistance due to pulmonary arterial smooth muscle cell (PASMC) contraction and proliferation.
• Upregulation of Transient Receptor Potential Canonical 6 (TRPC6) channels in PASMCs contributes to elevated cytosolic Ca2+ concentration ([Ca2+ ]cyt), driving vasoconstriction and proliferation.
• Currently, no selective and orally bioavailable TRPC6 antagonists are available for PAH/PH treatment.

Purpose of the Study:

• To investigate the efficacy of blocking TRPC6 channels in reversing established pulmonary hypertension (PH) in a mouse model.
• To evaluate the therapeutic potential of a selective TRPC6 blocker, BI-749327, and a nonselective cation channel blocker, 2-aminoethyl diphenylborinate (2-APB).

Main Methods:

• Intrapulmonary administration of 2-APB or BI-749327 to assess inhibition of hypoxia-induced pulmonary vasoconstriction.
• Treatment of mice with established PH via intraperitoneal injection of 2-APB or oral gavage of BI-749327.
• Assessment of pulmonary vascular remodeling and phosphorylation of AKT and mTOR in PASMCs.

Main Results:

• Both 2-APB and BI-749327 significantly inhibited acute hypoxia-induced pulmonary vasoconstriction.
• BI-749327 (oral) reversed established PH by approximately 50% through regression of pulmonary vascular remodeling.
• 2-APB (intraperitoneal) attenuated PH development and partially reversed established PH.
• Both agents inhibited PDGF- and serum-mediated phosphorylation of AKT and mTOR in PASMCs.

Conclusions:

• TRPC6 channels are a viable therapeutic target for PH and PAH.
• The selective TRPC6 blocker BI-749327 demonstrates significant potential as an effective oral drug for treating PH, including PAH and PH secondary to respiratory diseases or hypoxemia.