title: Calpain inhibition decreases inflammatory protein expression in vessel walls in a model of chronic myocardial ischemia.
abstract: Emerging data suggest a link between calpain activation and the enhanced inflammatory response of the cardiovascular system. We hypothesize that calpain activation associates with altered inflammatory protein expression in correlation with the proinflammatory profile of the myocardium. Our pig hypercholesterolemic model with chronic myocardial ischemia was treated with calpain inhibitors to establish their potential to improve cardiac function.
  
  
  
  Yorkshire swine, fed a high cholesterol diet for 4 weeks then underwent placement of an ameroid constrictor on the left circumflex artery. Two weeks later, animals received either no drug (high-cholesterol control group, n = 8), a low dose of calpain inhibitors (0.12 mg/kg, n = 9), or a high dose of calpain inhibitors (0.25 mg/kg; n = 8). The high-cholesterol diet and calpain inhibitors were continued for 5 weeks, after which the pig was euthanized. The left ventricular myocardial tissue (ischemic and nonischemic) was harvested and analyzed for inflammatory protein expression. Data were statistically analyzed via the Kruskal-Wallis and Dunn post hoc test.
  
  
  
  Calpain inhibitor treatment coincides with increased expression of IKB-α and decreased expression of macrophages, NFkB, IL-1, and tumor necrosis factor (TNF)-α in the ischemic myocardial tissue as compared with the control group. An NFkB array revealed decreased expression of IRF5, JNK1/2, JNK2, CD18, NFkB p65, c-Rel, Sharpin, TNF R1, TNF R2, and DR5 in the ischemic myocardium of the group treated with a high dose of calpain inhibitors compared with the control.
  
  
  
  Calpain activation in metabolic syndrome is a potential contributor to cardiac dysfunction in metabolic disorders with ischemic background. We suggest that calpain inhibition downregulates NFkB signaling in the vessel walls, which might be useful for improving myocardial blood flow in ischemic conditions.
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI.
authors.forename: Brittany A
authors.initials: BA
authors.lastname: Potz
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI.
authors.forename: Ashraf A
authors.initials: AA
authors.lastname: Sabe
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI.
authors.forename: Nassrene Y
authors.initials: NY
authors.lastname: Elmadhun
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI.
authors.forename: Sharif A
authors.initials: SA
authors.lastname: Sabe
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI.
authors.forename: Benedikt J V
authors.initials: BJV
authors.lastname: Braun
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Clements
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI.
authors.forename: Anny
authors.initials: A
authors.lastname: Usheva
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI. Electronic address: fsellke@lifespan.org.
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D000818:Animals; D002908:Chronic Disease; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006023:Glycoproteins / Q000627:therapeutic use*; D018836:Inflammation Mediators / Q000378:metabolism; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism*; D013552:Swine
chemical_list: D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D006023:Glycoproteins; D018836:Inflammation Mediators; C039304:calpain inhibitors