Department of Surgery, University of Colorado Denver, Aurora, CO, United States.
Front Immunol. 2022 Apr 14;13:891570. doi: 10.3389/fimmu.2022.891570. eCollection 2022.
This study tested the hypothesis that Toll-like receptor 2 (TLR2) augments the inflammatory responses and adverse remodeling in aging hearts to exacerbate myocardial injury and cardiac dysfunction.
Old (20-22 months old) and adult (4-6 months old) mice of C57BL/6 wild-type and TLR2 knockout (KO) were subjected to coronary artery ligation (30 minutes) and reperfusion (3 or 14 days). Left ventricle function was assessed using a pressure-volume microcatheter. Cardiac infarct size was determined by histology. Levels of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), matrix metalloproteinase 9 (MMP 9), and collagen I in non-ischemic myocardium were assessed by immunoblotting. Monocyte chemoattractant protein-1 (MCP-1), keratinocyte chemoattractant (KC), and interleukin-6 (IL-6) levels in ischemic and non-ischemic myocardium were measured by enzyme-linked immunosorbent assay (ELISA). TLR2 expression in the myocardium of untreated wild type mice was also measured by immunoblotting.
Higher levels of MCP-1, KC, IL-6 were induced in both ischemic and non-ischemic myocardium of old wild type mice at day 3 and 14 following ischemia/reperfusion (I/R) than those of adult wild type mice. The hyper-inflammatory responses to I/R in aging hearts were associated with elevated levels of myocardial TLR2. TLR2 KO markedly down-regulated the expression of MCP-1, KC, IL-6, ICAM-1 and VCAM-1 in aging hearts at day 3 and 14 following I/R. The down-regulated inflammatory activity in aging TLR2 KO hearts was associated with attenuated production of MMP 9 and collagen I at day 14 and resulted in reduced infarct size and improved cardiac function.
Elevated expression of myocardial TLR2 contributes to the mechanism by which aging exacerbates the inflammatory responses, adverse remodeling and cardiac dysfunction following myocardial I/R in aging.
本研究旨在验证 Toll 样受体 2（TLR2）是否会增强衰老心脏的炎症反应和不良重构，从而加剧心肌损伤和心功能障碍。
将 20-22 月龄（老年）和 4-6 月龄（成年）的 C57BL/6 野生型和 TLR2 敲除（KO）小鼠进行冠状动脉结扎（30 分钟）和再灌注（3 天或 14 天）。使用压力-容积微导管评估左心室功能。通过组织学确定心肌梗死面积。通过免疫印迹法评估非缺血心肌中血管细胞黏附分子-1（VCAM-1）、细胞间黏附分子-1（ICAM-1）、基质金属蛋白酶 9（MMP9）和胶原 I 的水平。通过酶联免疫吸附试验（ELISA）测量缺血和非缺血心肌中单核细胞趋化蛋白-1（MCP-1）、角质细胞趋化因子（KC）和白细胞介素-6（IL-6）的水平。还通过免疫印迹法测量未经处理的野生型小鼠心肌中 TLR2 的表达。
与成年野生型小鼠相比，老年野生型小鼠在缺血/再灌注（I/R）后第 3 天和第 14 天，缺血和非缺血心肌中 MCP-1、KC、IL-6 的水平更高。衰老心脏对 I/R 的高炎症反应与心肌 TLR2 水平升高有关。TLR2 KO 在 I/R 后第 3 天和第 14 天明显下调了衰老心脏中 MCP-1、KC、IL-6、ICAM-1 和 VCAM-1 的表达。衰老 TLR2 KO 心脏中下调的炎症活性与 MMP9 和胶原 I 在第 14 天的产生减少有关，导致梗死面积减小和心功能改善。
心肌 TLR2 的高表达有助于衰老加剧心肌 I/R 后炎症反应、不良重构和心功能障碍的机制。
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