Research On The Protective Effects Of Fatty Acid Synthase Inhibitors On The Development Of PAH

Background Pulmonary arterial hypertension(PAH)is a malignant cardiovascular disease with complex etiology and high lethality.The main manifestation is a progressive increase in pulmonary artery pressure,which can lead to pulmonary vascular remodeling,right heart hypertrophy,right heart failure and even death.Although the pathogenesis of PAH is still unclear,early studies have shown that inflammation and immune imbalance play an important role in the development of PAH.Clinically,the disordered proliferation of pulmonary arterial smooth muscle cells(PAMSCs)in PAH patients is a major pathological feature;and the pathophysiological characteristics of PAMSCs(such as loss of control of proliferation,inhibition of apoptosis,etc.)are very similar to tumorigenesis.Fatty acid synthase(FAS)is a key molecule catalyzing the synthesis of fatty acids.FAS has been shown to be highly expressed in various malignant tumors.Because it promotes the synthesis of endogenous fatty acids in tumor cells,synthetic fatty acids can provide substances and energy for the rapid proliferation of tumor cells.In addition,free fatty acids can activate the classical NF-?B inflammatory signaling pathway in vitro and in vivo.In recent years,studies have shown that inhibition of FAS can reduce PAH vascular remodeling by inducing apoptosis and inhibiting proliferation of PAMSCs.Therefore,we attempted to use the FAS inhibitor C75 to explore its effect on inflammation-related factors in PAH and its mechanism,thus sought potential therapeutic clues for the treatment of PAH.Purpose By observing FAS inhibitor C75 on the degree of cardiac hypertrophy,pathological changes of lung tissue and expression of inflammation-related factors in lung tissue induced by monocrotaline(MCT)in PAH mouse model,this study explores the inhibition of FAS can mediate the protective effect of PAH through inflammation-related factors.Method MCT induced PAH model,8 weeks old C57bl6 mice(25 in total),were divided into control group(intraperitoneal injection of normal saline),MCT group(intraperitoneal injection of MCT + normal saline),C75 intervention group(intraperitoneal MCT + different concentrations of FAS Inhibitor C75),the total molding time is 5 weeks.(1)After the end of modeling,measure right ventricular pressure and improve echocardiography to evaluate right ventricular hypertrophy;(2)Taking lung tissue to make pathological sections,Masson staining to detect changes in pulmonary small blood vessel structure;(3)Real-time quantitative PCR and Western Blot were used to detect the expression of IL-1?,IL-6,TNF-? and other cytokines and FAS in lung tissue.Result Compared with the normal control group,the pathological sections of the lung tissue of MCT group showed significant thickening of the pulmonary artery wall,stenosis of the lumen,and a large number of inflammatory cell infiltration.The pathological section of the lung tissue of C75 group was clear and the lumen was narrow,and inflammatory cell infiltration is significantly reduced.The protein expression levels of FAS and IL-1? in lung tissue of MCT group was significantly higher than that of the control group,while the protein expression of the above substances in C75(50?g/ml)group was lower than that in MCT group,the difference was statistically significant(P<0.05).The mRNA expression levels of FAS and TNF-? in lung tissue of mice in MCT group were significantly higher than those in control group,while the mRNA expression level of these substances in C75(50?g/ml)group was lower than that in MCT group,The difference was statistically significant(P<0.05).Conclusion The results of this study showed that FAS inhibitor C75 can alleviate pulmonary vascular inflammation and vascular remodeling in MCT-induced PAH mouse model,reduce the levels of various inflammatory factors,and thus slow the development of pulmonary hypertension.