Bacillus Calmette-Guérin and TLR4 agonist prevent cardiovascular hypertrophy and fibrosis by regulating immune microenvironment.
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.
Liu
Yu-Ying
YY
Molecular Immunology and Pharmacology Laboratory, Institute of Meteria Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Cai
Wen-Feng
WF
Yang
Hong-Zhen
HZ
Cui
Bing
B
Chen
Zhi-Rong
ZR
Liu
Han-Zhi
HZ
Yan
Jun
J
Jin
Wen
W
Yan
Hui-Min
HM
Xin
Bing-Mu
BM
Yuan
Bin
B
Hua
Fang
F
Hu
Zhuo-Wei
ZW
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
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