Deficiency of mouse mast cell protease 4 mitigates cardiac dysfunctions in mice after myocardium infarction

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1865

Article

Wang, Yunzhe^1,2,3  Liu, Cong-Lin^1,2,3  Fang, Wenqian^2,3  Zhang, Xian^2,3  Yang, Chongzhe^2,3  Li, Jie^2,3  Liu, Jing^2,3  Sukhova, Galina K.^2,3  Gurish, Michael F.^2,3  Libby, Peter^2,3  Shi, Guo-Ping^1,2,3  Zhang, Jinying¹ 

[1] Zhengzhou Univ, Key Lab Cardiac Injury & Repair Henan Prov, Affiliated Hosp 1, Dept Cardiol, Zhengzhou 450000, Henan, Peoples R China

[2] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA

[3] Harvard Med Sch, Boston, MA 02115 USA

关键词: mMCP4;    Myocardial infarction;    Cardiomyocyte;    Fibroblast;    Apoptosis;    Fibrosis;   

DOI  :  10.1016/j.bbadis.2019.01.011

来源: Elsevier

【 摘 要 】

Mouse mast cell protease-4 (mMCP4) is a chymase that has been implicated in cardiovascular diseases, including myocardial infarction (MI). This study tested a direct role of mMCP4 in mouse post-MI cardiac dysfunction and myocardial remodeling. Immunoblot and immunofluorescent double staining demonstrated mMCP4 expression in cardiomyocytes from the infarct zone from mouse heart at 28 day post-MI. At this time point, mMCP4-defident Mcpt4-1- mice showed no difference in survival from wild-type (WT) control mice, yet demonstrated smaller infarct size, improved cardiac functions, reduced macrophage content but increased T-cell accumulation in the infarct region compared with those of WT littermates. mMCP4-deficiency also reduced cardiomyocyte apoptosis and expression of TGF-131, p-Smad2, and p-Smad3 in the infarct region, but did not affect collagen deposition or a-smooth muscle actin expression in the same area. Gelatin gel zymography and immunoblot analysis revealed reduced activities of matrix metalloproteinases and expression of cysteinyl cathepsins in the myocardium, macrophages, and T cells from Mcpt4-/- mice. Immunoblot analysis also found reduced p-Smad2 and p-Smad3 in the myocardium from Mcpt4-/- mice, yet fibroblasts from Mcpt4-/- mice showed comparable levels of p-Smad2 and p-Smad3 to those of WT fibroblasts. Flow cytometry, immunoblot analysis, And immunofluorescent staining demonstrated that mMCP4-deficiency reduced the expression of proapoptotic cathepsins in cardiomyocytes and protected cardiomyocytes from H202-induced apoptosis. This study established a role of mMCP4 in mouse post-MI dysfunction by regulating myocardial protease expression and cardiomyocyte death without significant impact on myocardial fibrosis or survival post-MI in mice.

【 授权许可】

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