A Preliminary Study Of The Role Of TRPA1 In Monocrotaline-induced Pulmonary Arterial Hypertension In Rats

Research background and purpose:Pulmonary arterial hypertension(PAH)is a pathophysiological condition of abnormally elevated pulmonary artery pressure caused by many known or unknown factors.At present,the etiology and pathogenesis of PAH are complicated and multicausal.The mechanisms of PAH mainly include vascular remodeling and metabolic disorder,endothelial dysfunction and vasoconstriction,perivascular inflammation and thrombosis.Inflammation plays a very important role in many pathogenesis.In recent years,a lot of research has been done on the mechanism of PAH,and a series of therapeutic drugs have been found,which has made great progress in the treatment of PAH.However,due to the complicated mechanism of PAH,the existing drugs still have great limitations.TRPA1 plays an important role in inflammatory diseases such as atherosclerosis,chronic obstructive pulmonary disease,asthma,skin inflammation,osteoarthritis,etc.The pathogenesis of PAH has a certain relationship with inflammation.Therefore,TRPA1 may affect the development of PAH by influencing the inflammatory reaction.Research has revealed that TRPA1 can induce NOS to release NO,thus inducing smooth muscle relaxation.TRPA1 may reduce pulmonary vascular resistance by mediating the release of NO,thus delaying the progress of PAH.In this thesis,the effects of TRPA1 agonists and antagonists on pulmonary vascular tissue in rats with PAH were studied by establishing a rat model of PAH,and the role of TRPA1 in the development of PAH was discussed,which can provide a new direction for its treatment.Materials and Methods:1.Experimental objects and grouping: male SD rats were selected as experimental objects,and randomly divided into control group(Control),model group(MCT),and intervention group;in order to observe the role of TRPA1 in PAH rats,respectively give TRPA1 agonist(cinnamaldehyde)and TRPA1 antagonist(HC-030031)to interfere with MCT-induced rats.2.Research methods: The physical condition of the rats was assessed by observing their hair,body weight,mental and activity levels;the RVSP and m PAP were measured by right heart catheterization;the right ventricle and septum + left ventricle were separated and weighed separately to calculate the RVHI;the expression of TRPA1 in pulmonary arterioles was detected by immunohistochemistry and Western blot;HE staining,expression of PCNA in pulmonary arterioles was examined by immunofluorescence staining and western blot;Masson staining was used to assess the degree of fibrosis in pulmonary arterioles;immunohistochemistry was used to detect α-SMA and CD68 expression was measured by immunohistochemistry to assess the degree of myelination of pulmonary arterioles.Result:1.Successful establishment of pulmonary hypertension model,the expression of TRPA1 in pulmonary arterioles was decreased in the MCT group.Cinnamaldehyde intervened in MCT-induced rats to increase the expression of TRPA1 in pulmonary arterioles.HC-030031 intervened in MCT-induced rats to decrease the expression of TRPA1 in pulmonary arterioles.2.Cinnamaldehyde,a TRPA1 agonist,had no significant effect on the body weight of rats induced by MCT.Cinnamaldehyde decreased the RVSP,m PAP,RVHI induced by MCT in rats.Cinnamaldehyde alleviated the degree of vascular stenosis and smooth muscle hyperplasia and hypertrophy of pulmonary arterioles induced by MCT,alleviated the degree of pulmonary arterioles fibrosis,and decreased the expression of PCNA,α-SMA and CD68 in pulmonary arterioles.3.HC-030031,a TRPA1 antagonist,had no significant effect on the body weight of rats induced by MCT.HC-030031 increased the RVSP,m PAP,RVHI induced by MCT.HC-030031 aggravates the degree of vascular stenosis and smooth muscle hyperplasia and hypertrophy of pulmonary arterioles induced by MCT,aggravates the degree of pulmonary arterioles fibrosis,and increases the expression of PCNA,α-SMA and CD68 in pulmonary arterioles.Conclusion:1.The rat model of PAH was successfully established by monocrotaline intervention.TRPA1 was expressed in the pulmonary arterioles of normal rats,but decreased in monocrotaline-induced PAH rats.2.Activation of TRPA1 improves the degree of proliferation,myelination,and fibrosis of pulmonary arterioles in rats with PAH,which may alleviate right ventricular hypertrophy and reduce the level of inflammation,while inhibition of TRPA1 does the opposite.TRPA1 may be a potential target to delay the progression of PAH.