Department of Geriatrics, Jiangsu Provincial Key Laboratory of Geriatrics, First Affiliated Hospital of Nanjing Medical University, Guangzhou Rd. 300, Nanjing, China.
Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Cardiovasc Res. 2019 Jan 1;115(1):154-167. doi: 10.1093/cvr/cvy163.
Inadequate healing after myocardial infarction (MI) leads to heart failure and fatal ventricular rupture, while optimal healing requires timely induction and resolution of inflammation. This study tested the hypothesis that heat shock protein B1 (HSPB1), which limits myocardial inflammation during endotoxemia, modulates wound healing after MI.
To test this hypothesis, cardiomyocyte-specific HSPB1 knockout (Hspb1-/-) mice were generated using the Cre-LoxP recombination system. MI was induced by ligation of the left anterior descending coronary artery in Hspb1-/- and wild-type (WT) littermates. HSPB1 was up-regulated in cardiomyocytes of WT animals in response to MI, and deficiency of cardiomyocyte HSPB1 increased MI-induced cardiac rupture and mortality within 21 days after MI. Serial echocardiography showed more aggravated remodelling and cardiac dysfunction in Hspb1-/- mice than in WT mice at 1, 3, and 7 days after MI. Decreased collagen deposition and angiogenesis, as well as increased MMP2 and MMP9 activity, were also observed in Hspb1-/- mice compared with WT controls after MI, using immunofluorescence, polarized light microscopy, and zymographic analyses. Notably, Hspb1-/- hearts exhibited enhanced and prolonged leucocyte infiltration, enhanced expression of inflammatory cytokines, and enhanced TLR4/MyD88/NFκB activation compared with WT controls after MI. In-depth molecular analyses in both mice and primary cardiomyocytes demonstrated that cardiomyocyte-specific knockout of HSPB1 increased nuclear factor-κB (NFκB) activation, which promoted the expression of proinflammatory mediators. This led to increased leucocyte recruitment, thereby to excessive inflammation, ultimately resulting in adverse remodelling, cardiac dysfunction, and cardiac rupture following MI.
These data suggest that HSPB1 acts as a negative regulator of NFκB-mediated leucocyte recruitment and the subsequent inflammation in cardiomyocytes. Cardiomyocyte HSPB1 is required for wound healing after MI and could be a target for myocardial repair in MI patients.
心肌梗死 (MI) 后愈合不良可导致心力衰竭和致命性心室破裂，而最佳愈合则需要及时诱导和解决炎症。本研究旨在检验以下假说：热休克蛋白 B1（HSPB1）在脓毒症期间限制心肌炎症，是否能调节 MI 后的伤口愈合。
为了验证这一假说，我们使用 Cre-LoxP 重组系统生成了心肌细胞特异性 HSPB1 敲除（Hspb1-/-）小鼠。通过结扎左前降支冠状动脉诱导 Hspb1-/-和野生型（WT）同窝仔鼠的 MI。WT 动物的心肌细胞在 MI 后 HSPB1 上调，而心肌细胞 HSPB1 的缺失则增加了 MI 后 21 天内的心脏破裂和死亡率。心脏超声心动图显示，MI 后 1、3 和 7 天，Hspb1-/-小鼠的心脏重构和心功能恶化程度比 WT 小鼠更严重。MI 后，免疫荧光、偏光显微镜和酶谱分析显示，与 WT 对照组相比，Hspb1-/-小鼠的胶原沉积和血管生成减少，MMP2 和 MMP9 活性增加。值得注意的是，与 WT 对照组相比，Hspb1-/-心脏在 MI 后表现出更强和更持久的白细胞浸润、炎症细胞因子表达增强以及 TLR4/MyD88/NFκB 激活增强。在小鼠和原代心肌细胞的深入分子分析中，我们发现心肌细胞特异性 HSPB1 敲除增加了核因子-κB（NFκB）的激活，从而促进了促炎介质的表达。这导致白细胞募集增加，进而导致过度炎症，最终导致 MI 后不良重构、心功能障碍和心脏破裂。
这些数据表明，HSPB1 作为 NFκB 介导的白细胞募集和随后的心肌细胞炎症的负调节剂发挥作用。MI 后，心肌细胞 HSPB1 是伤口愈合所必需的，可能成为 MI 患者心肌修复的靶点。
