CsA Ameliorates Right Ventricular Hypertrophy Induced By Pulmonary Arterial Hypertension In Rat Via Suppressing The Expressions Of Lumican And HSP20

Background and Aims: Pulmonary arterial hypertension(PAH)is one of the five types of pulmonary hypertension(PH),the main pathological features of PAH are proliferation and dysfunction of pulmonary arterial endothelium and smooth muscle cells,meanwhile,accompanied by infiltration of inflammatory cells and thrombosis.These pathological changes increase pulmonary vascular resistance(PVR),leading to the development of PAH.The sustained pressure overload further leads to right ventricular hypertrophy(RVH)and even right ventricular failure,which can eventually result in death without effective and timely treatment.The prognosis of PAH patients is not only related to the level of pulmonary arterial pressure,but also depends on the adaptability and compensatory ability of the right heart.However,there is currently no clinical treatment that can directly or selectively improve the function of right ventricle.At present,the treatment of PAH is mainly to improve the symptoms of patients and prolong the survival time of patients by dilating pulmonary vessels,but can not fundamentally improve the survival rate of patients.Therefore,there is an urgent need to elucidate the molecular mechanisms of right ventricular hypertrophy and failure with PAH,and to seek potential molecular therapeutic targets.Cyclosporin A(CsA)is an immunosuppressant,which can inhibit the immune response and inflammatory response.Clinically,CsA is often used for organ transplantation and the treatment of autoimmune diseases.The purpose of this study was to investigate the preventive and therapeutic effects of CsA on right ventricular hypertrophy induced by PAH and its potential molecular mechanisms.Methods:(1)Rats were intraperitoneally injected with Monocrotaline(MCT)at one time,and then given different doses of CsA(6.25,12.5,25 mg/kg)intraperitoneally once a day.Three weeks later,right ventricular systolic pressure(RVSP)and right ventricular mass index(RVMI)were measured in each group,and HE staining of lung tissue was used to detect pulmonary vascular remodeling.Then,right ventricular function was evaluated by echocardiography,pathological changes of right ventricular cardiomyocytes were observed by HE staining and WGA staining of paraffin section of heart tissue,and right ventricular fibrosis was observed by masson staining.Finally,the expression levels of cardiac hypertrophy and fibrosis related genes in the samples were determined by q RT-PCR.The preventive effects of CsA on MCT induced PAH and right ventricular hypertrophy were comprehensively evaluated by the above methods.(2)After two weeks of intraperitoneal injection of MCT,rats were treated with CsA(25 mg/kg/d)for two weeks.At the end of the animal experiment,right ventricular function of rats was evaluated by echocardiography,and then RVSP,RVMI and other data were measured in each group.HE staining was performed on rat lung tissue.At the same time,HE,WGA and masson staining were performed on the heart tissue of the rats.Finally,q RT-PCR was used to determine the expression levels of cardiac hypertrophy and fibrosis related genes in the samples.The therapeutic effect of CsA on MCT induced PAH and right ventricular hypertrophy was comprehensively evaluated by the above methods.(3)Target proteins were screened by proteomics analysis.Western Blot was used to verify the reliability of the results.Results:(1)In the rat model of MCT,with the increase of CsA dose,RVMI could gradually return to normal level,but RVSP could not always return to normal,and pulmonary vessel wall remodeling could not be completely inhibited.Echocardiography,pathological staining and q RT-PCR further confirmed that CsA prophylactic administration could completely inhibit right ventricular hypertrophy induced by MCT and maintain right ventricular function at normal level.(2)CsA treatment for 2 weeks can partially reduce the rise of RVSP in MCT rats,reduce the degree of pulmonary vascular remodeling,completely improve the cardiomyocyte hypertrophy and fibrosis of right ventricle,and restore the function of right ventricle to normal level.(3)Lumican and HSP20 were significantly upregulated in the MCT model,while their expression levels were significantly down-regulated after CsA preventive administration.And Lumican was located in the core region of the protein interaction network.Conclusions: In summary,CsA can inhibit or reverse the occurrence and development of PAH and RVH induced by MCT in rats,and has a more significant protective effect on the right ventricle.Lumican and HSP20 may be involved in the occurrence and development of RVH in MCT rats,and CsA may protect the right ventricle by regulating these two proteins.