Inactivation of carboxyl terminus of Hsc70-interacting protein prevents hypoxia-induced pulmonary arterial smooth muscle cells proliferation by reducing intracellular Ca2+ concentration.

Abstract

Carboxyl terminus of Hsc70-interacting protein (CHIP) is a 35-kDa cytoplasmic protein expressed in human striated muscle, brain, aortic smooth muscle, endothelial cells, and other tissues. Studies have confirmed that CHIP regulates cell growth, apoptosis, cell phenotype, metabolism, neurodegeneration, etc. However, whether CHIP is involved in pulmonary artery smooth muscle cell (PASMC) proliferation, a vital contributor to chronic hypoxia-induced pulmonary hypertension (CHPH), remains unknown. In this study, we first evaluated CHIP expression in the pulmonary arteries (PAs) of CHPH model rats. Subsequently, by silencing CHIP, we investigated the effect of CHIP on hypoxia-induced PASMC proliferation and the underlying mechanism. Our results showed that CHIP expression was upregulated in the PAs of CHPH model rats. Silencing CHIP significantly suppressed the hypoxia-triggered promotion of proliferation, [Ca2+]i, store-operated Ca2+ entry (SOCE), and some regulators of SOCE such as TRPC1 and TRPC6 in cultured PASMCs. These results indicate that CHIP likely contributes to hypoxia-induced PASMC proliferation by targeting the SOCE-[Ca2+]i pathway through the regulation of TRPC1 and TRPC6 in the PASMCs. In conclusion, the findings of the current study clarify the role of CHIP in hypoxia-induced PASMC proliferation.