Sodium Houttuyfonate Alleviates Monocrotaline-induced Pulmonary Hypertension by Regulating Orai1 and Orai2.

Abstract

An increased intracellular Ca²⁺ concentration ([Ca²⁺]_i) is a key trigger for pulmonary arterial smooth muscle cell (PASMC) proliferation and contributes greatly to pulmonary hypertension (PH). Extracellular Ca²⁺ influx via a store-operated Ca²⁺ channel, termed store-operated Ca²⁺ entry (SOCE), is a crucial mechanism for [Ca²⁺]_i increase in PASMCs. Calcium release-activated calcium modulator (Orai) proteins, consisting of three members (Orai1-3), are the main components of the store-operated Ca²⁺ channel. Sodium houttuyfonate (SH) is a product of the addition reaction of sodium bisulfite and houttuynin and has antibacterial, antiinflammatory, and other properties. In this study, we assessed the contributions of Orai proteins to monocrotaline (MCT)-enhanced SOCE, [Ca²⁺]_i, and cell proliferation in PASMCs and determined the effect of SH on MCT-PH and the underlying mechanism, focusing on Orai proteins, SOCE, and [Ca²⁺]_i in PASMCs. Our results showed that: 1) Orai1 and Orai2 were selectively upregulated in the distal pulmonary arteries and the PASMCs of MCT-PH rats; 2) knockdown of Orai1 or Orai2 reduced SOCE, [Ca²⁺]_i, and cell proliferation without affecting their expression in PASMCs in MCT-PH rats; 3) SH significantly normalized the characteristic parameters in a dose-dependent manner in the MCT-PH rat model; and 4) SH decreased MCT-enhanced SOCE, [Ca²⁺]_i, and PASMC proliferation via Orai1 or Orai2. These results indicate that SH likely exerts its protective role in MCT-PH by inhibiting the Orai1,2-SOCE-[Ca²⁺]_i signaling pathway.