Key Laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, PR China; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Oncology, Affiliated Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200223, China.
J Mol Cell Cardiol. 2019 Feb;127:44-56. doi: 10.1016/j.yjmcc.2018.11.010. Epub 2018 Nov 19.
Extracellular matrix metabolism and cardiac cell death participate centrally in myocardial infarction (MI). This study tested the roles of collagenolytic cathepsin K (CatK) in post-MI left ventricular remodeling.
Patients with acute MI had higher plasma CatK levels (20.49 ± 7.07 pmol/L, n = 26) than those in subjects with stable angina pectoris (8.34 ± 1.66 pmol/L, n = 28, P = .01) or those without coronary heart disease (6.63 ± 0.84 pmol/L, n = 93, P = .01). CatK protein expression increases in mouse hearts at 7 and 28 days post-MI. Immunofluorescent staining localized CatK expression in cardiomyocytes, endothelial cells, fibroblasts, macrophages, and CD4 T cells in infarcted mouse hearts at 7 days post-MI. To probe the direct participation of CatK in MI, we produced experimental MI in CatK-deficient mice (Ctsk) and their wild-type (Ctsk) littermates. CatK-deficiency yielded worsened cardiac function at 7 and 28 days post-MI, compared to Ctsk littermates (fractional shortening percentage: 5.01 ± 0.68 vs. 8.62 ± 1.04, P < .01, 7 days post-MI; 4.32 ± 0.52 vs. 7.60 ± 0.82, P < .01, 28 days post-MI). At 7 days post-MI, hearts from Ctsk mice contained less CatK-specific type-I collagen fragments (10.37 ± 1.91 vs. 4.60 ± 0.49 ng/mg tissue extract, P = .003) and more fibrosis (1.67 ± 0.93 vs. 0.69 ± 0.20 type-III collagen positive area percentage, P = .01; 14.25 ± 4.12 vs. 6.59 ± 0.79 α-smooth muscle actin-positive area percentage, P = .016; and 0.82 ± 0.06 vs. 0.31 ± 0.08 CD90-positive area percentage, P = .008) than those of Ctsk mice. Immunostaining demonstrated that CatK-deficiency yielded elevated cardiac cell death but reduced cardiac cell proliferation. In vitro studies supported a role of CatK in cardiomyocyte survival.
Plasma CatK levels are increased in MI patients. Heart CatK expression is also elevated post-MI, but CatK-deficiency impairs post-MI cardiac function in mice by increasing myocardial fibrosis and cardiomyocyte death.
细胞外基质代谢和心肌细胞死亡是心肌梗死（MI）的核心参与因素。本研究旨在探讨组织蛋白酶 K（CatK）在 MI 后左心室重构中的作用。
急性 MI 患者的血浆 CatK 水平（20.49±7.07 pmol/L，n=26）高于稳定性心绞痛患者（8.34±1.66 pmol/L，n=28，P=0.01）或无冠心病患者（6.63±0.84 pmol/L，n=93，P=0.01）。MI 后 7 天和 28 天，小鼠心脏中的 CatK 蛋白表达增加。免疫荧光染色显示，MI 后 7 天，CatK 在梗死小鼠心脏中的心肌细胞、内皮细胞、成纤维细胞、巨噬细胞和 CD4 T 细胞中表达。为了探究 CatK 在 MI 中的直接参与作用，我们在 CatK 缺陷型（Ctsk）和野生型（Ctsk）同窝仔鼠中产生实验性 MI。与 Ctsk 同窝仔鼠相比，CatK 缺陷型仔鼠在 MI 后 7 天和 28 天的心脏功能更差（短轴缩短率百分比：5.01±0.68 vs. 8.62±1.04，P<0.01，7 天；4.32±0.52 vs. 7.60±0.82，P<0.01，28 天）。MI 后 7 天，Ctsk 仔鼠心脏中 CatK 特异性 I 型胶原片段减少（10.37±1.91 vs. 4.60±0.49 ng/mg 组织提取物，P=0.003），纤维化程度增加（III 型胶原阳性面积百分比：1.67±0.93 vs. 0.69±0.20，P=0.01；α-平滑肌肌动蛋白阳性面积百分比：14.25±4.12 vs. 6.59±0.79，P=0.016；CD90 阳性面积百分比：0.82±0.06 vs. 0.31±0.08，P=0.008）。免疫染色显示，CatK 缺陷型仔鼠心肌细胞死亡增加，而细胞增殖减少。体外研究支持 CatK 在心肌细胞存活中的作用。
MI 患者的血浆 CatK 水平升高。MI 后心脏 CatK 表达也升高，但 CatK 缺陷型通过增加心肌纤维化和心肌细胞死亡，损害 MI 后小鼠的心脏功能。
