Calpain Inhibition Decreases Myocardial Fibrosis in Chronically Ischemic Hypercholesterolemic Swine

Abstract Objectives 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. Methods 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. Results In the setting of hypercholesterolemia and chronic myocardial ischemia, CI decreased the expression of collagen in ischemic and non-ischemic 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. Conclusions Calpain inhibition may be a beneficial medical therapy to decrease collagen formation in patients with coronary artery disease and associated co-morbidities.