Carter Kelly, Shah Eshan, Waite Jessica, Rana Dhruv, Zhao Zhi-Qing
Cardiovascular Research Laboratory, Mercer University School of Medicine, Savannah, GA 31404, USA.
Cells. 2024 Dec 4;13(23):2001. doi: 10.3390/cells13232001.
Heart failure is a complex syndrome characterized by cardiac hypertrophy, fibrosis, and diastolic/systolic dysfunction. These changes share many pathological features with significant inflammatory responses in the myocardium. Among the various regulatory systems that impact on these heterogeneous pathological processes, angiotensin II (Ang II)-activated macrophages play a pivotal role in the induction of subcellular defects and cardiac adverse remodeling during the progression of heart failure. Ang II stimulates macrophages via its AT1 receptor to release oxygen-free radicals, cytokines, chemokines, and other inflammatory mediators in the myocardium, and upregulates the expression of integrin adhesion molecules on both monocytes and endothelial cells, leading to monocyte-endothelial cell-cell interactions. The transendothelial migration of monocyte-derived macrophages exerts significant biological effects on the proliferation of fibroblasts, deposition of extracellular matrix proteins, induction of perivascular/interstitial fibrosis, and development of hypertension, cardiac hypertrophy and heart failure. Inhibition of macrophage activation using Ang II AT1 receptor antagonist or depletion of macrophages from the peripheral circulation has shown significant inhibitory effects on Ang II-induced vascular and myocardial injury. The purpose of this review is to discuss the current understanding in Ang II-induced maladaptive cardiac remodeling and dysfunction, particularly focusing on molecular signaling pathways involved in macrophages-mediated hypertension, cardiac hypertrophy, fibrosis, and failure. In addition, the challenges remained in translating these findings to the treatment of heart failure patients are also addressed.
心力衰竭是一种复杂的综合征，其特征为心脏肥大、纤维化以及舒张/收缩功能障碍。这些变化与心肌中显著的炎症反应具有许多共同的病理特征。在影响这些异质性病理过程的各种调节系统中，血管紧张素II（Ang II）激活的巨噬细胞在心力衰竭进展过程中诱导亚细胞缺陷和心脏不良重塑方面起着关键作用。Ang II通过其AT1受体刺激巨噬细胞，使其在心肌中释放氧自由基、细胞因子、趋化因子和其他炎症介质，并上调单核细胞和内皮细胞上整合素黏附分子的表达，导致单核细胞与内皮细胞之间的相互作用。单核细胞衍生的巨噬细胞经内皮迁移对成纤维细胞增殖、细胞外基质蛋白沉积、血管周围/间质纤维化的诱导以及高血压、心脏肥大和心力衰竭的发展具有显著的生物学效应。使用Ang II AT1受体拮抗剂抑制巨噬细胞激活或从外周循环中清除巨噬细胞，已显示出对Ang II诱导的血管和心肌损伤具有显著的抑制作用。本综述的目的是讨论目前对Ang II诱导的适应性不良心脏重塑和功能障碍的理解，特别关注巨噬细胞介导的高血压、心脏肥大、纤维化和衰竭所涉及的分子信号通路。此外，还讨论了将这些研究结果转化为心力衰竭患者治疗方法时仍然存在的挑战。
