Macrophage-mediated regulation of catecholamines in sympathetic neural remodeling after myocardial infarction
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ORIGINAL CONTRIBUTION
Macrophage‑mediated regulation of catecholamines in sympathetic neural remodeling after myocardial infarction Juanjuan Lyu1 · Man Wang2,3 · Xinjiang Kang4 · Huadong Xu4 · Zhongming Cao5 · Tao Yu3,6 · Keli Huang3,6 · Jin Wu1 · Xinchuan Wei2,3 · Qian Lei2,3 Received: 12 March 2020 / Accepted: 20 July 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Sympathetic neural remodeling, which involves the inflammatory response, plays an important role in ventricular arrhythmias (VAs) after myocardial infarction (MI). Adrenergic receptors on macrophages potentially modulate the inflammatory response. We hypothesized that the increased level of catecholamines activates macrophages and regulates sympathetic neural remodeling after MI. We treated MI mice with either clodronate or metoprolol for 5 days following coronary artery ligation. Mice without treatment after MI and sham-operation mice served as the positive control and negative control, respectively. The norepinephrine levels in plasma and the peri-infarct myocardium increased by almost two-fold in the MI mice compared with the sham-operation mice. Both in vivo and ex vivo electrophysiology examinations showed that the vulnerability to VAs induced by MI was alleviated by macrophage depletion with clodronate and β1-adrenergic blockade with metoprolol, which was in line with circulating and peri-infarct norepinephrine levels, sympathetic reinnervation, and the expression of nerve growth factor (NGF) 7 days after surgery. To further verify the interaction between catecholamines and macrophages, we preconditioned lipopolysaccharide-stimulated RAW 264.7 cells using epinephrine or epinephrine with selective adrenergic antagonists. The expression and release of inflammatory factors including NGF were enhanced by epinephrine. This effect was inhibited by metoprolol but not by other subtype antagonists. Our data suggested that the increased level of catecholamines, traditionally known as positive inotropes secreted from sympathetic nerve endings, might regulate cardiac sympathetic neural remodeling through β1-adrenergic receptors on macrophages, subsequently inducing VAs after MI. Keywords Myocardial infarction · Arrhythmia · Sympathetic nerve · Catecholamine · Macrophage
Introduction It is widely known that survivors of myocardial infarction (MI) remain at high risk for ventricular arrhythmias (VAs) and cardiogenic sudden death [40]. The infarct myocardium * Xinchuan Wei [email protected] * Qian Lei [email protected] 1
Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China
2
Anesthesia and Operation Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
3
School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, China
and scar produce anatomical substrates that promote cardiac arrhythmias [17], and the altered sy
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