Mechanism Of STIM 1/Orai 1 Pathway In The Abnormal Proliferation And Migration Of Coronary Artery Smooth Muscle Cells Induced By Hypertensive State

Hypertension is the most common chronic disease,The damage to target organs such as the heart,brain and kidneys caused by it can increase the incidence of coronary heart disease,stroke,and other cardiovascular and cerebrovascular diseases,bringing huge physical and psychological burden and economic burden to human beings..Coronary heart disease is one of the most important target organ damage in hypertension.Epidemiological surveys show that about 60% of coronary heart disease patients in China have hypertension,and the risk of coronary heart disease in people with hypertension is 4 times higher than that in people without hypertension.The occurrence and development of coronary heart disease are closely related to hypertension and vascular dysfunction.The research on the related molecular mechanisms has received more and more attention.OBJECTIVE:To explore the possible pathogenesis of coronary heart disease caused by hypertension by observing the effect of high-pressure loading on the changes of phenotypic transformation and expression of contractile-associated proteins and the proliferation of coronary vascular smooth muscle cells(VSMCs).METHODS:Ten male SPF and 16-week-old male SHR and Wistar rats were selected.The rats were sacrificed by carbon dioxide,the heart was quickly removed,left and right coronary arteries were separated by stereomicroscope,and the structural changes of hypertension coronary artery were observed by hematoxylin-eosin(HE)staining.Changes of Orai1 expression in coronary artery of hypertensive patients by immunohistochemical method.Then the coronary VSMCs of SHR and Wistar rats were cultured by tissue adherent method.Partially used for Western blot to detect the phenotype marker of coronary artery in two groups: α-smooth muscle actin(α-SMA),smooth muscle Globular heavy chain(SM-MHC),smooth muscle 22 α(SM22 α),osteopontin(OPN)and related protein:matrix interaction molecule(STIM1),Orai1,L-type calcium channel(Cav1.2),calcium/calpatophosphatase(Calcineurin),the protein expression level of activated T-cell nuclear factor(NFAT).Some coronary VSMCs from Wistar rats were treated with high hydrostatic pressure for 24 hours,and the expression of these proteins was detected by Western blot.The other part of the coronary VSMCs with cell count(CCK-8)observed the effect of different pressure on the number of cells,and β-galactosidase(β-gal)kit staining observed two groups of rat coronary The effect of arterial VSMCs on cell senescence.RESULTS:(1)HE staining showed that the smooth muscle cells of the Wistar group were arranged neatly,the elastic fibers of the media had no proliferation,and the inner membrane was uniform.However,in the SHR group,the thickness of the coronary artery was thickened,the smooth muscle cells were arranged disorderly,the morphology was irregular,and the endothelial cells were arranged.disorder.(2)The expression of Orai1 in hypertensive coronary VSMCs was increased by immunohistochemistry.(3)The expression of SM-MHC and related proteins Cav1.2and NFAT2 were significantly down-regulated in SHR coronary VSMCs,and the expression of the synthetic phenotypic marker OPN and related proteins STIM1,Orai1,and Calcineurin was significantly upregulated(4).)After treatment of coronary VSMCs for 24 h with high hydrostatic pressure(0mmHg,120 mmHg,180mmHg),the expression of SM-MHC,α-SMA,Cav1.2 protein in the 120 mmHg and 180 mmHg groups and NFAT2 protein expression in the 180 mmHg group was greater than 0mmHg.The group was significantly down-regulated;OPN and Calcineurin protein expression in 120 mmHg group and 180 mmHg group and Slim1,Orai1 protein expression in 180 mmHg group were significantly higher than those in0 mmHg group;(5)VSMCs in the SHR group had higher proliferative capacity at24 h,48h,and 72 h than the same generation.The Wistar group was significantly reduced,but the percentage of cell senescence was significantly increased.(6)After treatment of coronary VSMCs with high hydrostatic pressure for 24 h,the proliferative capacity of 120 mmHg group and 180 mmHg group at 48 h was significantly lower than that of 0 mmHg group.CONCLUSION:Hypertension may activate the STIM1,increase the expression of Orai1 channel,and activate the calcineurin-NFAT signaling pathway,which leads to phenotypic changes in coronary VSMCs,leading to changes in coronary artery function and ultimately to coronary atherosclerosis.