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Molecular Immunology and Pharmacology Laboratory, Institute of Meteria Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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-
, 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-/TGF-β in the heart. The cardiac protective effects of BCG and TLR4 agonist are related to their regulation of ERK-Akt and p38-NF-
B 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the National Major Basic Research Program of China (2006CB503808) and from National Nature Scientific Foundation (30672468). Z.-W.H. is also supported by Cheung-Kong Scholars Programme of Ministry of Education and by a Senior Oversea Chinese Scholar Fund from Ministry of Personnel of China.
2 Y.-Y.L. and W.-F.C. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Zhuo-Wei Hu, Institute of Meteria Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China. E-mail address: huzhuowei{at}imm.ac.cn
4 Abbreviations used in this paper: BCG, bacillus Calmette-Guérin; AAC, abdominal aortic constriction; LV, left ventricle; DC, dendritic cell; ASP, arterial systolic pressure; ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; dp/dt, derivative of pressure.
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