Function Of Store-operated Ca²⁺ Channels In New Rat Model Of Pulmonary Hypertension

Objective: We study the function of store-operated Ca2+ channels(SOCC) in the pathogenesis of PH, applying the left lobectomy(pneumonectomy, PE) plus subcutaneous injection of monocrotaline(MCT) induced pulmonary hypertension rats, to find new targets for the clinical treatment of PH.Methods: The SD rats underwent unilateral lobectomy, extubate tracheal catheter after spontaneous breathing recovery. 1 week later, rats were intraperitoneal injected of 2%MCT(50 mg/kg), feeding 3wk, to form chronic pulmonary hypertension rat model. We measured by hemodynamics indexes mean right ventricular pressure(m RVP); right ventricular mass index,(RVMI); and the lung section HE staining to identify PH rat model. Then we detected TRPC1 m RNA expression by real-time RT-PCR; Futher more we tested SOCC agonist cyclopiazonic acid(CPA) induced pulmonary arteries(PAs) contraction and Ca2+ entry in pulmonary artery smooth muscle cells(PASMCs); meanwhile we observed the effect of endothelin-1(ET-1) induced vasocontration, and the relaxation of gadolinium(Gd3+) on ET-1 induced PAs contraction.Results: ① successfully established PE plus MCT induced PH rat model :m RVP and RVMI were significantly increased in PE and PE+MCT group(P<0.01), suggesting that PE and PE+MCT can induced severe PH and right ventricular hypertrophy; HE stain showed pulmonary vascular smooth muscles was hyperplasia significantly, pulmonary artery diameter was decreased, indicating that PE+MCT remodeled the structure of pulmonary artery; ②target gene expression was increased: PE+ MCT upregulated target gene-TRPC1 m RNA expression; ③upregulation of SOCE: compared with CON rats, SOCC agonist CPA induced significant increase in PAs contraction(P<0.01) and dramatic enhancement in PASMCs Ca2+ entries in PE+MCT rats(P<0.01);④vasoconstriction caused by 10 n M ET-1 in PE and PE+MCT groups were significantly higher than that in CON group, and 3n M Gd3+ induced relaxation were more significant in PE and PE+MCT PH rats.Conclusion: PE+MCT upregulated TRPC1 expression, and enhanced TRPC1 mediated SOCE function, which play an important role in high tension of PH pulmonary artery. TRPC1/SOCC may be a new target for clinical treatment of pulmonary hypertension related diseases.