Establishment Of An Animal Model Of Pulmonary Hypertension Induced By Methamphetamine And Its Mechanism

Background:Methamphetamine(methamphetamine,METH),commonly known as "ice",has a benzene ring structure,which is very similar to the structure of catecholamine neurotransmitters.It is a new type of amphetamine psychostimulant that has toxic effects on all tissues and organs of the body.More neurotoxicity and cardiovascular toxicity of METH.Pulmonary hypertension is a highly malignant progressive disease characterized by a progressive increase in pulmonary artery resistance,which leads to an increase in the right heart afterload and eventually death due to right heart failure.Its main pathological features are vasospasm of pulmonary arterioles,pulmonary artery intimal hyperplasia and vascular remodeling.Many current studies have shown that long-term abuse of METH is closely related to the occurrence of pulmonary hypertension,but the specific molecular mechanism of action is still unclear.Objectives:This study mainly discusses the method of establishing the animal model of METH-induced pulmonary hypertension,and preliminarily explores the mechanism of STIM1 in METH-induced pulmonary hypertension.The aim is to provide a suitable animal model for the study of METH-induced pulmonary hypertension,and to provide a theoretical basis for the study of its related molecular regulation mechanisms and therapeutic targets.Methods:Collect lung tissue specimens of long-term METH addicts,use HE and Masson staining to observe the pathological changes of lung tissue,and detect the expression of STIM1 molecule by immunohistochemistry and immunofluorescence.A mouse model of pulmonary hypertension induced by chronic METH was established.Masson staining and HE staining were used to observe histopathological changes of pulmonary artery.In vitro METH(primary cultured rat pulmonary artery cells)poisoning model was constructed,and the phenotypic transition,proliferation and STIM1 of smooth muscle cells after METH treatment were detected by scratch experiment,cell growth curve,Western Blot,immunohistochemistry,and immunofluorescence.Express the situation.After inhibiting the expression of STIM1,the changes in phenotypic transition of pulmonary vascular smooth muscle cells,proliferation-related molecules and signaling pathway proteins were detected.To study the effect of METH on the contraction,proliferation and migration of pulmonary vascular smooth muscle cells after exposure to pulmonary artery smooth muscle cells.Results:1.Long-term METH users can see obvious thickening of the vascular media layer of the lung tissue and remodeling of the pulmonary blood vessels.2.The long-term effect of METH successfully induced a mouse pulmonary hypertension model.3.In the vitro pulmonary vascular smooth muscle cell poisoning model,the ability of cell proliferation and migration in the METH group was significantly enhanced by the scratch test and cell growth curve determination,the expression of a-SMA and SM22a was significantly down-regulated,and the expression of PCNA was significantly increased.4.After METH treatment,the expression of STIM1 was significantly up-regulated.After suppressing the expression of STIMl/Orail,the intracellular calcium ion overload was inhibited,smooth muscle cells could be restored from synthetic type to contractile type,and the proliferation ability decreased,indicating that STIM1 regulates intracellular calcium ion concentration through the Orai1 pathway Participate in METH-induced pulmonary artery remodeling.