The Protective Effect Of Yiqi Fumai Lyophilized Injection On Chronic Heart Failure And Its Proteomic Analysis

Yiqi Fumai lyophilized injection（YQFM）is a modern traditional Chinese medicine preparation,which was developed by Shengmai Powder and approved by the China Food and Drug Administration for clinical in 2012.It is widely used in the treatment of ischemic heart failure and hypertrophic obstructive cardiomyopathy.Considerable evidences have showed that YQFM is composed of Ginseng Radix Et Rhizoma Rubra,Schisandrae Chinensis Fructus and Ophiopogonis Radix.65compounds have been identified,including 21 active components such as Re,Rg₃,Rh₁,Rb₁,Rb₃,ophiopogonins and ligans quantified.This study was divided into three parts:1.The protective effect of Yiqi Fumai Lyophilized Injection on chronic heart failure.Existing clinical studies have shown that YQFM can availably alleviate the clinical symptoms of chronic heart failure（CHF）patients,however,complexity of traditional Chinese medicine（TCM）prescriptions and various causes of CHF inhibits the clinical utility.The purpose of this study was to investigate the myocardial protective effects of YQFM against abdominal aortic coarctation（AAC）-induced chronic heart failure and explore the mechanisms which mediated by inflammation,mitochondrial energy metabolism,reactive oxygen species（ROS）and apoptosis.The AAC-induced CHF rats were treated with YQFM（273 mg/kg,546 mg/kg and 1092mg/kg i.p.respectively）for 28 days.After YQFM treatment,the echocardiography and histological findings of cardiac were obviously meliorated.According to the research,YQFM could recover the damage of heart via downregulating the contents of inflammatory markers,increasing the number of mitochondria,repairing the morphology of mitochondria,enhancing the respiratory condition of mitochondria,repairing the activity of antioxidant and preventing the expression of apoptosis related proteins.Results showed that YQFM allenuated AAC-induced CHF by ameliorating heart function,reducing ROS production,increasing mitochondrial energy metabolism,preventing excessive inflammation and apoptosis.2.Proteomic analysis reveals the protective effects of Yiqi Fumai Lyophilized Injection on abdominal aorta coarctation induced chronic heart failure in rats.YQFM has the characteristics of multi-component and multi-target,which can treat CHF through a variety of ways.Therefore,it is necessary to further study its most prominent mechanism of action in the treatment of CHF.The purpose of this study was to proteomics methods to explore the protective mechanism of YQFM in rats with AAC.After YQFM treatment,the echocardiography of cardiac were obviously meliorated compared with the model group rat.A total of 157 important differentially expressed proteins（DEPs）were identified,including 109 in model rat compared with that in control rat（M:C）and 48 in YQFM-treated rat compared with that in model rat（T:M）by i TRAQ technology to analyze the proteomic characteristics of heart tissue.Bioinformatics analysis showed that DEPs was mainly involved in the body’s energy metabolism and was closely related to oxidative phosphorylation.Furthermore,Western blot analysis showed that the expressions of peroxisome proliferator-activated receptor-γcoactivator-1α（PGC-1α）,perixisome proliferation-activated receptor alpha（PPAR-α）and retinoid X receptor alpha（RXR-α）were upregulated,PGC-1αas well as its downstream effectors,including nuclear respiratory factor 1（NRF-1）and mitochondrial transcription factor A（Tfam）was also found to be upregulated in cardiomyocytes after YQFM treatment.These results provided evidence that YQFM could enhance mitochondrial function and ameliorate mitochondrial energy metabolism of cardiomyocytes to play a role in the treatment of CHF by regulating mitochondrial biogenesis-related proteins.3.Nanoparticle Conjugation of ginsenoside Rb₃ inhibits myocardial fibrosis by regulating PPARαpathway.Cardiac fibrosis occurs in ischemic and non-ischemic heart failure,hereditary cardiomyopathy,diabetes and aging.Energy metabolism,which serves a crucial function in the course and treatment of cardiovascular diseases,might have therapeutic benefits for myocardial fibrosis.Ginsenoside Rb₃（G-Rb₃）is one of the main components of Ginseng and exhibits poor oral bioavailability but still exerts regulate energy metabolism effects in some diseases.Therefore,the study investigated the effect of chitosan（CS）@sodium tripolyphosphate（TPP）nanoparticles conjugation with ginsenoside Rb₃（Np Rb₃）on myocardial fibrosis,and explored the effect of Np Rb₃ on the PPARα/RXRαcascade and subsequent targets.First of all,Np Rb₃ can improve the cardiac function of HF rat model and change its pathological changes.Second,in vitro studies have shown that Np Rb₃ can protect the proliferation of cardiac fibroblasts stimulated by AngⅡ.The results showed that Np Rb₃ directly participates in the remodeling of myocardial energy metabolism and the regulation of PPARα,thereby improving the degree of myocardial fibrosis.The study also verifies the protective effect of Np Rb₃ on energy metabolism and mitochondrial function by targeting the PPARαpathway.