Cardiomyocyte-Specific Deficiency of HSPB1 Worsens Cardiac Dysfunction by Activating NFκB-Mediated Leucocyte Recruitment After Myocardial Infarction
Aims 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. Methods and results 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. Conclusion 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.
Wang, Yana; Liu, Jiali; Kong, Qiuyue; Cheng, Hao; Tu, Fei; Yu, Peng; Liu, Ying; Zhang, Xiaojin; Li, Chuanfu; Li, Yuehua; Min, Xinxu; Du, Shuya; Ding, Zhengnian; and Liu, Li. 2019. Cardiomyocyte-Specific Deficiency of HSPB1 Worsens Cardiac Dysfunction by Activating NFκB-Mediated Leucocyte Recruitment After Myocardial Infarction. Cardiovascular Research. Vol.115(1). 154-167. https://doi.org/10.1093/cvr/cvy163 PMID: 29982352 ISSN: 0008-6363