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Macrophage depletion protects against endothelial dysfunction and cardiac remodeling in angiotensin II hypertensive
Yuantong Tian1, Jun Luo2, Qian Xu3
1The Open Project of Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, P.R. of China.
Insights
Depleting cardiac macrophages with liposome encapsulated clodronate (LEC) reduced hypertension-induced cardiac hypertrophy and fibrosis in mice. This suggests macrophages play a key role in hypertensive heart remodeling.
Area of Science:
- Cardiovascular Science
- Immunology
- Pharmacology
Background:
- Hypertension is linked to low-grade systemic inflammation.
- Macrophage infiltration in the heart can drive vascular and ventricular remodeling in hypertension.
Purpose of the Study:
- To investigate the impact of chemical macrophage depletion on cardiac hypertrophy and remodeling in angiotensin II-induced hypertensive mice.
Main Methods:
- Angiotensin II infusion in C57BL/6 mice to induce hypertension.
- Treatment with liposome encapsulated clodronate (LEC) to deplete macrophages.
- Assessment of blood pressure, cardiac hypertrophy, fibrosis, and endothelium-dependent relaxation.
Main Results:
- Angiotensin II increased blood pressure, cardiac hypertrophy, fibrosis, and macrophage infiltration, while impairing endothelium-dependent relaxation.
- LEC treatment significantly reduced cardiac hypertrophy, fibrosis, and macrophage infiltration, and improved endothelium-dependent relaxation.
- LEC treatment decreased inflammatory cytokines and profibrotic factors, and inhibited MAPK pathway activation.
Conclusions:
- Cardiac macrophages are critical in hypertensive cardiac hypertrophy and remodeling.
- Macrophage depletion may mitigate cardiac damage through anti-inflammatory and anti-fibrotic mechanisms.
- Targeting cardiac macrophages could be a therapeutic strategy for hypertensive heart disease.
Abstract:
Objective: Hypertension is associated with a low-grade systemic inflammation in cardiovascular system. Macrophage infiltration may initiate an inflammatory process that contributes to vascular and ventricular remodeling in hypertensive human and mice. The present study investigated the effect of chemical depletion of macrophage using liposome encapsulated clodronate (LEC) on cardiac hypertrophy and remodeling in angiotensin (Ang) II hypertensive mice.Methods: C57BL/6 mice received an Ang II (1.1 mg/kg/day with a minipump) infusion for 2 weeks to induce hypertension. Endothelium-dependent relaxation (ED) was examined by organ bath, hematoxylin and staining and Masson-Trichrome staining were used to evaluate aorta and cardiac hypertrophy and fibrosis.Results: Ang II infusion significantly increased systolic blood pressure (SBP), cardiac hypertrophy and fibrosis, and impaired EDR accompanied by increased macrophage infiltration in the heart. Treatment with LEC significantly lowered Ang II-induced cardiac hypertrophy and fibrosis and cardiac macrophage infiltration, and improved EDR with a mild reduction in SBP. Ang II increased the expression of inflammatory cytokines tumor necross factor alpha and interleukin 1 beta and profibrotic factors transforming growth factor beta 1 and fibronectin in the heart, with was reduced by LEC treatment. Treatment with LEC prevented Ang II-induced the phosphorphorylation of ERK1/2 and c-Jun-N-terminal kinase.Conclusions: Our study suggests that cardiac macrophage may be critical for hypertensive cardiac hypertrophy and remodeling, the underlying mechanisms may involve initial heart inflammation and the activation of hypertrophic MAPKs pathway.
