Sodium Tanshinone IIA Sulfonate Inhibits Canonical Transient Receptor Potential Expression in Pulmonary Arterial Smooth Muscle from Pulmonary Hypertensive Rats
Sodium Tanshinone IIA Sulfonate Inhibits Canonical Transient Receptor Potential Expression in Pulmonary Arterial Smooth Muscle from Pulmonary Hypertensive Rats
复制标题
丹参酮IIA磺酸钠抑制肺动脉高压大鼠肺动脉平滑肌典型瞬时受体电位表达
DOI：
10.1165/rcmb.2012-0071oc
复制
发表时间：
2013-01-01
影响因子：
6.4
通讯作者：
Lu, Wenju
中科院分区：
文献类型：
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作者：
Wang, Jian;Jiang, Qian;Lu, Wenju
丹参是丹参的干燥根，在中国临床上广泛用于治疗多种疾病，包括心血管疾病。丹参酮 IIA 磺酸钠 (STS) 是从丹参中分离出来的主要活性成分丹参酮 IIA 的水溶性衍生物，最近报道可有效减轻与慢性缺氧性肺动脉高压 (CHPH) 相关的特征性肺血管变化；然而，人们对潜在的详细机制知之甚少。在本研究中，我们研究了 STS 对暴露于长期缺氧或从 CHPH 大鼠中分离的远端肺动脉平滑肌细胞 (PASMC) 的基础细胞内 Ca2+ 浓度 ([Ca2+](i)) 和储存操纵的 Ca2+ 进入 (SOCE) 的影响。慢性缺氧（10% O-2，21 d）大鼠 PASMC 中 Fura-2 荧光的 Mn2+ 猝灭测量 SOCE 增加 59%，基础 [Ca2+](i) 增加 119%；腹腔注射STS可抑制这种作用。 STS 对 SOCE 和基础 [Ca2+](i) 缺氧增加的抑制作用与远端肺动脉平滑肌中典型瞬时受体电位 (TRPC) 1 和 TRPC6 表达减少以及右心室压力降低、右心室肥厚和外周肺血管增厚相关。在离体培养的常氧大鼠远端 PASMC 中，STS (0-25 μM) 剂量依赖性地抑制缺氧诱导的细胞增殖和迁移，同时减弱基础 [Ca2+](i)、SOCE、mRNA 和 TRPC1 和 TRPC6 蛋白表达的增加。在野百合碱诱导的肺动脉高压大鼠模型中，STS 还可以减轻右心室收缩压、右心室肥厚以及远端肺动脉中 TRPC1 和 TRPC6 蛋白的表达。这些结果表明，STS 可能通过抑制 TRPC1 和 TRPC6 表达来预防肺动脉高压的发生，导致基础 [Ca2+](i) 正常化并减弱 PASMC 的增殖和迁移。
Danshen, the dried root of Salvia miltiorrhiza, is widely used in clinics in China for treating various diseases, including cardiovascular diseases. Sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA isolated as the major active component from Danshen, was recently reported to be effective in attenuating the characteristic pulmonary vascular changes associated with chronically hypoxic pulmonary hypertension (CHPH); however, the underlying detailed mechanisms are poorly understood. In this study, we investigated the effects of STS on basal intracellular Ca2+ concentration ([Ca2+](i)) and store-operated Ca2+ entry (SOCE) in distal pulmonary arterial smooth muscle cells (PASMCs) exposed to prolonged hypoxia or isolated from CHPH rats. SOCE measured by Mn2+ quenching of Fura-2 fluorescence in PASMCs from rats exposed to chronic hypoxia (10% O-2, 21 d) was increased by 59%, and basal [Ca2+](i) was increased by 119%; this effect was inhibited by intraperitoneal injection of STS. These inhibitory effects of STS on hypoxic increases of SOCE and basal [Ca2+](i) were associated with reduced expression of canonical transient receptor potential (TRPC) 1 and TRPC6 in distal pulmonary arterial smooth muscle and decreases on right ventricular pressure, right ventricular hypertrophy, and peripheral pulmonary vessel thickening. In ex vivo cultured distal PASMCs from normoxic rats, STS (0-25 mu M) dose-dependently inhibited hypoxia induced cell proliferation and migration, paralleled with attenuation in increases of basal [Ca2+](i), SOCE, mRNA, and protein expression of TRPC1 and TRPC6. STS also relieved right ventricular systolic pressure, right ventricular hypertrophy, and TRPC1 and TRPC6 protein expression in distal pulmonary arteries in a monocrotaline-induced rat model of pulmonary arterial hypertension. These results indicate that STS prevents pulmonary arterial hypertension development likely by inhibiting TRPC1 and TRPC6 expression, resulting in normalized basal [Ca2+](i) and attenuated proliferation and migration of PASMCs.