Bacillus Calmette-Guérin and TLR4 agonist prevent cardiovascular hypertrophy and fibrosis by regulating immune microenvironment
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Yu-Ying Liu1, Wen-Feng Cai, Hong-Zhen Yang
1Molecular Immunology and Pharmacology Laboratory, Institute of Meteria Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Insights
Bacillus Calmette-Guérin (BCG) and TLR4 agonists prevent hypertension-induced cardiac hypertrophy and fibrosis by modulating immune responses and signaling pathways. These findings highlight potential therapeutic strategies for heart failure prevention.
Area of Science:
- Cardiology
- Immunology
- Pathology
Background:
- Hypertension-induced cardiovascular hypertrophy and fibrosis are key contributors to heart failure.
- Toll-like receptors (TLRs) are implicated in pressure overload-induced cardiac remodeling.
Purpose of the Study:
- To investigate if bacillus Calmette-Guérin (BCG), a TLR4 activator, could prevent cardiac hypertrophy and fibrosis in a murine model of hypertension.
- To explore the role of TLR4 in mediating these protective effects.
Main Methods:
- Murine model of abdominal aortic constriction (AAC)-induced hypertension.
- Administration of BCG, TLR4 agonist, IFN-gamma, or TLR4 antagonist before or after AAC.
- Assessment of cardiovascular hypertrophy, cardiac fibrosis, hemodynamics, TLR expression, cytokine ratios (IFN-gamma/TGF-beta), and key signaling pathways (ERK-Akt, p38-NF-kappaB).
Main Results:
- BCG and TLR4 agonist significantly prevented AAC-induced cardiovascular hypertrophy and fibrosis without altering hemodynamics.
- TLR4 antagonist reversed the protective effects of BCG and TLR4 agonist.
- BCG modulated TLR expression on heart tissue, while TLR4 agonist increased TLR expression on infiltrating immune cells, leading to an increased IFN-gamma/TGF-beta ratio.
- Cardiac protection involved the regulation of ERK-Akt and p38-NF-kappaB signaling pathways.
Conclusions:
- TLR4 activity is critical in mediating pressure overload-induced myocardial hypertrophy and fibrosis.
- BCG and TLR4 agonists demonstrate potential for preventing and treating hypertension-induced cardiac hypertrophy and fibrosis through immune response modulation.
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.
