Elevated intracellular Ca2+ concentration ([Ca2+]i), resulting from store-operated calcium entry (SOCE), serves as a pivotal trigger for the proliferation of pulmonary arterial smooth muscle cells (PASMCs) and plays a crucial role in the pathogenesis of pulmonary hypertension (PH). As the crucial constituents of the store-operated Ca2+ channel (SOCC), canonical transient receptor potential channel (TRPC) proteins, particularly TRPC1, TRPC4, and TRPC6 are upregulated in monocrotaline-induced PH (MCT-PH). Sodium houttuyfonate (SH) is a compound derived from the combination of sodium bisulfite and houttuynin, and has been scientifically proven to possess a wide range of antibacterial, anti-inflammatory, and cardiovascular protective properties. In this study, we investigated the contributions of TRPC1, TRPC4, and TRPC6 to MCT-enhanced SOCE-[Ca2+]i and PASMC proliferation. Furthermore, based on the actions of TRPC1, TRPC4 and TRPC6, we explored the mechanism by which SH mitigates MCT-PH. The results revealed that: 1) TRPC1, TRPC4, and TRPC6 played significant roles in MCT-induced enhancement of SOCE-[Ca2+]i and PASMC proliferation; 2) SH exhibited suppressive effects on the expression levels of TRPC1, TRPC4, TRPC6 and NF-κB in distal pulmonary arteries (PAs) and cultured PASMCs. 3) Overexpression of either TRPC1, TRPC4 or TRPC6 attenuated the inhibitory effect of SH on MCT-elevated SOCE-[Ca2+]i and PASMC proliferation. 4) SH down-regulated the interaction between STIM1 and TRPC1, TRPC4 or TRPC6 in distal PAs and cultured PASMCs from MCT-PH model rats. The present findings provide compelling evidence that SH effectively mitigates MCT-PH by inhibiting PASMC proliferation through the TRPC1,4,6-SOCE-[Ca2+]i pathway, likely mediated by NF-κB and STIM1.
Keywords: MCT-PH; PASMCs; SOCE; Sodium houttuyfonate; [Ca(2+)](i).
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