Calpain inhibition decreases myocardial fibrosis in chronically ischemic hypercholesterolemic swine

J Thorac Cardiovasc Surg. 2022 Jan;163(1):e11-e27. doi: 10.1016/j.jtcvs.2019.11.150. Epub 2020 Mar 29.

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 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.

Conclusions: Calpain inhibition may be a beneficial medical therapy to decrease collagen formation in patients with coronary artery disease and associated comorbidities.

Keywords: Jak/STAT/MCP-1 signaling; TGF-beta; chronic myocardial ischemia; collagen; fibrosis calpain inhibitor; hypercholesterolemia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calpain / metabolism*
  • Chemokine CCL2 / metabolism
  • Collagen* / biosynthesis
  • Collagen* / metabolism
  • Coronary Artery Disease / drug therapy
  • Coronary Artery Disease / metabolism
  • Disease Models, Animal
  • Fibrosis / etiology
  • Fibrosis / metabolism
  • Fibrosis / prevention & control
  • Glycoproteins / pharmacology*
  • Hypercholesterolemia / metabolism
  • Janus Kinase 2 / metabolism
  • Myocardial Ischemia / metabolism*
  • Myocardium* / metabolism
  • Myocardium* / pathology
  • STAT Transcription Factors / metabolism
  • Signal Transduction / drug effects
  • Swine
  • Ventricular Remodeling* / drug effects
  • Ventricular Remodeling* / physiology

Substances

  • Chemokine CCL2
  • Glycoproteins
  • STAT Transcription Factors
  • calpain inhibitors
  • Collagen
  • Janus Kinase 2
  • Calpain