Abstract P2163: The Genetic And Pharmacological Inhibition Of Classic Transient Receptor Potential Channels 3 And 6 (trpc3/c6) Improve Pulmonary Arterial Hypertension.

Abstract

Background: Pulmonary artery hypertension (PAH) is a progressive and fatal disease. Currently, there are only three types of PAH drugs, targeting the endothelin pathway, NO pathway, and prostacyclin pathway, and all these drugs are pulmonary vasodilators. However, the pathogenesis of PAH develops through various mechanisms, including vascular endothelial dysfunction, pulmonary artery smooth muscle cell (PASMC) proliferation, fibrosis and inflammation as well as vasoconstriction. Recently, calcium signaling has been reported to be involved in these multiple mechanisms in PAH. Classic transient receptor potential channel 3 and 6 (TRPC3/C6), known as receptor-operated calcium channels, have been reported to be involved in the pathogenesis of PAH. Methods and Results: Initially, we evaluated TRPC3 knockout mice (TRPC3KO), TRPC6 knockout mice (TRPC6KO), and TRPC3/C6 double-knockout mice (dKO) in the PAH models, to evaluate the effects of genetic inhibition of TRPC3/C6. All of TRPC3KO, TRPC6KO, and dKO have weakened PAH phenotypes such as the systolic pulmonary artery pressure, the right ventricular hypertrophy, and the tunica media thickening of the pulmonary artery in monocrotaline pyrrole-induced PAH models. On the other hand, in the hypoxia-induced PAH model, TRPC6KO and dKO ameliorated these PAH phenotypes, but TRPC3KO didn’t. Next, we evaluated the effect of pharmacological inhibition of TRPC3/C6 in PAH model rats. We have developed a novel selective TRPC3/C6 inhibitor, L862. This compound showed excellent pharmacokinetic and safety properties. L862 ameliorated monocrotaline-induced and hypoxia-induced PAH in rat models on prevention protocol. Moreover, L862 significantly suppressed PDGF-BB-induced proliferation of human PASMC derived from idiopathic PAH patients in a dose-dependent manner. L862 also improved PAH in Sugen/hypoxia rat model on the therapeutic protocol. Conclusions: Both genetic and pharmacological inhibition of TRPC3/C6 ameliorated PAH in several PAH models. These results suggested that TRPC3/C6 had essential roles in the pathogenesis of PAH and L862 had potential clinical application.