Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI.
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI.
J Thorac Cardiovasc Surg. 2022 Jan;163(1):e11-e27. doi: 10.1016/j.jtcvs.2019.11.150. Epub 2020 Mar 29.
Calpain activation during ischemia is known to play critical roles in myocardial remodeling. We hypothesize that calpain inhibition (CI) may serve to reverse and/or prevent fibrosis in chronically ischemic myocardium.
Yorkshire swine were fed a high-cholesterol diet for 4 weeks followed by placement of an ameroid constrictor on the left circumflex artery to induce myocardial ischemia. 3 weeks later, animals received either: no drug; high-cholesterol control group (CON; n = 8); low-dose CI (0.12 mg/kg; LCI, n = 9); or high-dose CI (0.25 mg/kg; HCI, n = 8). The high-cholesterol diet and CI were continued for 5 weeks, after which myocardial tissue was harvested. Tissue samples were analyzed by western blot for changes in protein content.
In the setting of hypercholesterolemia and chronic myocardial ischemia, CI decreased the expression of collagen in ischemic and nonischemic myocardial tissue. This reduced collagen content was associated with a corresponding decrease in Jak/STAT/MCP-1 signaling pathway, suggesting a role for Jak 2 signaling in calpain activity. CI also decreases the expression of focal adhesion proteins (vinculin) and stabilizes the expression of cytoskeletal and structural proteins (N-cadherin, α-fodrin, desmin, vimentin, filamin, troponin-I). CI had no significant effect on metabolic and hemodynamic parameters.
Calpain inhibition may be a beneficial medical therapy to decrease collagen formation in patients with coronary artery disease and associated comorbidities.
已知钙蛋白酶在缺血期间的激活在心肌重构中起关键作用。我们假设钙蛋白酶抑制（CI）可能有助于逆转和/或预防慢性缺血心肌中的纤维化。
约克夏猪喂食高胆固醇饮食 4 周，然后在左回旋动脉上放置一个缩窄环以诱导心肌缺血。3 周后，动物接受以下治疗之一：无药物；高胆固醇对照组（CON；n=8）；低剂量 CI（0.12mg/kg；LCI，n=9）；或高剂量 CI（0.25mg/kg；HCI，n=8）。高胆固醇饮食和 CI 持续 5 周，然后收获心肌组织。通过 Western blot 分析组织样本中蛋白含量的变化。
在高胆固醇血症和慢性心肌缺血的情况下，CI 降低了缺血和非缺血心肌组织中胶原蛋白的表达。这种胶原蛋白含量的减少与 Jak/STAT/MCP-1 信号通路的相应减少有关，表明 Jak 2 信号在钙蛋白酶活性中起作用。CI 还降低了黏着斑蛋白（波形蛋白）的表达，并稳定了细胞骨架和结构蛋白（N-钙黏蛋白、α-辅肌动蛋白、结蛋白、波形蛋白、细丝蛋白、肌钙蛋白 I）的表达。CI 对代谢和血流动力学参数没有显著影响。
钙蛋白酶抑制可能是一种有益的医学治疗方法，可减少冠状动脉疾病和相关合并症患者的胶原蛋白形成。
