Alteration Of MRNA And Time-course Curve Of TRPC Pathway Signaling Molecules Of Pulmonary Artery In Chronic Hypoxia Pulmonary Hypertension Rats

Objective:Through investigating the significance of STIM-Orai-TRPC-CaN-NFATsignaling pathway in the development of chronic hypoxia pulmonary hypertension(PH) rats, exploring the function and mechanisms of the entire TRPC signal pathwayin the progress of chronic hypoxia PH rats, and comparing with the experimentalresult of the monocrotaline (MCT)-induced pulmonary arterial hypertension(PAH),we can provide new ideas and targets for the prevention and treatment of PH.Methods:The normal SD rats were exposed to atmospheric condition containing10%oxygen for3weeks to prepare the model of chronic hypoxia PH rats. We measured:①PH model identification: mean right ventricular pressure (mRVP)、 rightventricular weight index (RVMI)、right ventricular systolic pressure（RVSP）;②Real-time RT-PCR were used to examine the mRNA levels of related signalmolecules in this signal pathway, and depicted the time-cource curve of mRNA of thesignal molecules which have changes (detect respectively in chronic hypoxia1d、3d、5d、7d、14d、21d), so as to analyze the relationship between the alteration of theexpression of these signal molecules and the time-course curves of hemodynamicparameters (mRVP, RVMI).Results: Compared with the control group (CON group):①the mRVP、 RVMI andRVSP increase obviously in the model group (P<0.01), indicates that chronic hypoxiacan induce the PH and right ventricular hypertrophy in rats;②TRPC signalmolecules express widely in PAs of rats, only the expression of TRPC1and TRPC6 mRNA level increased after the precondition of chronic hypoxic3weeks;③in theupstream signal molecules (STIM and Orai), after the precondition of chronic hypoxic3weeks, the expression of STIM2, Orai2mRNA levels were increased, but theexpression of STIM1、Orai1and Orai3mRNA levels showed no significant change;④in the TRPC downstream signal molecules (CaN and NFAT), after theprecondition of chronic hypoxic3weeks, the expression of CaNBβand NFATc3mRNA levels increased, but the expression of CaNAα/β/γ、 CaNBα andNFATc1/NFATc2-NFATc4mRNA levels had no significant change;⑤when wedetected the time-course curves of the of mRNA expressionon levels whichexpression increased, we found that the expression of theSTIM2-Orai2-TRPC1/TRPC6-CaNB-NFATc3mRNA levels began to increase inchronic hypoxic early period (1d/3d), then it reached a plateau(5d/7d), andmaintained up to the third week; RVMI showed continue to increase, did not show aplateau; and the peak of RVSP appeared in2W, the up-regulation occurs before theincreasing of the RVMI and RVSP, suggesting that chronic hypoxia could induce PHby up-regulating the expression of STIM2-Orai2-TRPC1/6-CaNBβ-NFATc3,andeventually lead to right ventricular remodeling in rats.Conclusion: It is the precondition of chronic hypoxic for3weeks that may induce PHand pulmonary vascular remodeling through the up-regulation of theSTIM2-Orai2-TRPC1/6-CaNBβ-NFATc3mRNA levels; but has no effect on theexpression of signal molecules such as STIM1, Orai1, Orai3, CaNA/CaNBαNFATc1/NFATc2/NFATc4mRNA levels. After the precondition of chronic hypoxic,TRPC1/6and its related signal molecules (STIM2-Orai2-TRPC1/6-CaNBβ-NFATc3)elevated up before RVMI and RVSP. So this signaling pathway may be the key factorthat caused to the up-regulation of signaling molecules, and give rise to rightventricular hypertrophy,and right ventricular remodeling in the chronic hypoxia PHrats.