Mechanisms Of CD151 Mediated Angiogenesis Participates In The Alleviation Of Cardiac Fibrosis By Bovine Milk Exosomes

Background:Cardiac fibrosis is a pathological process characterized as excess extracellular matrix(ECM)deposition and contribute to nearly all types of heart disease,eventually leading to congestive heart failure.The underlying mechanism of cardiac fibrosis is still unclear,and cardiac fibrosis is a difficult clinical puzzle without evidence-based effective therapies.Bovine milk exosomes are compatible with animals or humans and can be obtained from bovine milk in scalable quantities.Meanwhile,bovine milk exosomes are very stable in the gastrointestinal tract and bioavailable by intragastric administration.Previous research has indicated that exosomes can significantly enhance angiogenesis in massive conditions,including cardiac fibrosis,myocardial infarction and spinal injury.The effect of bovine milk exosomes on cardiac fibrosis remains unclear.To test the therapeutic effect of cardiac fibrosis,we examined the effects of bovine milk exosomes on cardiac fibrosis both in isoproterenol(ISO)-induced cardiac fibrosis rats and in human umbilical vein endothelial cells(HUVECs)after oxygen and glucose deprivation(OGD).Methods:We established cardiac fibrosis model by injected subcutaneously with ISO,and cardiac fibrosis rats were intragastrically administrated with bovine milk exosomes.The levels of cardiac fibrosis were assessed by H&E staining,Masson staining,and western blot.The transthoracic echocardiography was selected to evaluate the cardiac function of rats.Moreover,the proangiogenic effects of bovine milk exosomes were analyzed both in ISO-induced cardiac fibrosis rats in vivo and HUVECs after OGD in vitro.The transcriptome sequencing of left ventricle was performed to explore changes in expression profiles of mRNA.Furthermore,RNAi was performed to screen and verify the target gene regulating angiogenesis concerning bovine milk exosomes on cardiac fibrosis.Results:Bovine milk exosomes alleviated the ECM deposition and enhanced the cardiac function in cardiac fibrosis rat.The proangiogenic growth factors were significantly enhanced accepted bovine milk exosomes.Meanwhile,bovine milk exosomes ameliorated the motility,migration,and tube forming ability of HUVECs after OGD in vitro.We identified 116 differently expressed mRNAs.DEMs were further validated by RT-qPCR.Then,we performed Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis of DEMs and DELs,showing that they were mainly enriched in circadian rhythms,immunologic activities,immunity.Conclusion:Bovine milk exosomes alleviate cardiac fibrosis and enhance cardiac function in cardiac fibrosis rats via enhancing angiogenesis.CD151 may be involved in the regulation of bovine milk exosomes on angiogenesis in rats with cardiac fibrosis,which may represent a potential strategy for the treatment of cardiac fibrosis.