title: Bacillus Calmette-Guérin and TLR4 agonist prevent cardiovascular hypertrophy and fibrosis by regulating immune microenvironment.
abstract: Hypertension-induced cardiovascular hypertrophy and fibrosis are critical in the development of heart failure. The activity of TLRs has been found to be involved in the development of pressure overload-induced myocardial hypertrophy and cardiac fibrosis. We wondered whether vaccine bacillus Calmette-Guérin (BCG), which activated TLR4 to elicit immune responses, modulated the pressure overload-stimulated cardiovascular hypertrophy and cardiac fibrosis in the murine models of abdominal aortic constriction (AAC)-induced hypertension. Before or after AAC, animals received BCG, TLR4 agonist, IFN-gamma, or TLR4 antagonist i.p. BCG and TLR4 agonist significantly prevented AAC-induced cardiovascular hypertrophy and reactive cardiac fibrosis with no changes in hemodynamics. Moreover, TLR4 antagonist reversed the BCG- and TLR4 agonist-induced actions of anti-cardiovascular hypertrophy and cardiac fibrosis. BCG decreased the expression of TLR2 or TLR4 on the heart tissue but TLR4 agonist increased the expression of TLR2 or TLR4 on the immune cells that infiltrate into the heart tissue. This led to an increased expression ratio of IFN-gamma/TGF-beta in the heart. The cardiac protective effects of BCG and TLR4 agonist are related to their regulation of ERK-Akt and p38-NF-kappaB signal pathways in the heart. In conclusion, the activity of TLR4 plays a critical role in the mediation of pressure overload-induced myocardial hypertrophy and fibrosis. The regulation of immune responses by BCG and TLR4 agonist has a great potential for the prevention and treatment of hypertension-induced myocardial hypertrophy and cardiac fibrosis.
authors.affiliation: Molecular Immunology and Pharmacology Laboratory, Institute of Meteria Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yu-Ying
authors.initials: YY
authors.lastname: Liu
authors.forename: Wen-Feng
authors.initials: WF
authors.lastname: Cai
authors.forename: Hong-Zhen
authors.initials: HZ
authors.lastname: Yang
authors.forename: Bing
authors.initials: B
authors.lastname: Cui
authors.forename: Zhi-Rong
authors.initials: ZR
authors.lastname: Chen
authors.forename: Han-Zhi
authors.initials: HZ
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.forename: Wen
authors.initials: W
authors.lastname: Jin
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Yan
authors.forename: Bing-Mu
authors.initials: BM
authors.lastname: Xin
authors.forename: Bin
authors.initials: B
authors.lastname: Yuan
authors.forename: Fang
authors.initials: F
authors.lastname: Hua
authors.forename: Zhuo-Wei
authors.initials: ZW
authors.lastname: Hu
mesh_terms: D000217:Acyltransferases / Q000494:pharmacology; D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage / Q000276:immunology*; D006332:Cardiomegaly / Q000276:immunology* / Q000517:prevention & control; D002319:Cardiovascular System / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D029968:Escherichia coli Proteins / Q000494:pharmacology; D005355:Fibrosis / Q000276:immunology / Q000517:prevention & control; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism
chemical_list: D001500:BCG Vaccine; D029968:Escherichia coli Proteins; D008070:Lipopolysaccharides; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma; D000217:Acyltransferases; C097895:MsbB protein, E coli; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases