title: Calpain inhibition improves collateral-dependent perfusion in a hypercholesterolemic swine model of chronic myocardial ischemia.
abstract: OBJECTIVE
  Calpain overexpression is implicated in aberrant angiogenesis. We hypothesized that calpain inhibition (MDL28170) would improve collateral perfusion in a swine model with hypercholesterolemia and chronic myocardial ischemia.
  
  
  METHODS
  Yorkshire swine fed a high cholesterol diet for 4 weeks underwent surgical placement of an ameroid constrictor to their left circumflex coronary artery. Three weeks later, animals received no drug, high cholesterol control group (n = 8); low-dose calpain inhibition (0.12 mg/kg; n = 9); or high-dose calpain inhibition (0.25 mg/kg; n = 8). The heart was harvested after 5 weeks.
  
  
  RESULTS
  Myocardial perfusion in ischemic myocardium significantly improved with high-dose calpain inhibition at rest and with demand pacing (P = .016 and .011). Endothelium-dependent microvessel relaxation was significantly improved with low-dose calpain inhibition (P = .001). There was a significant increase in capillary density, with low-dose calpain inhibition and high-dose calpain inhibition (P = .01 and .01), and arteriolar density with low-dose calpain inhibition (P = .001). Calpain inhibition significantly increased several proangiogenic proteins, including vascular endothelial growth factor (P = .02), vascular endothelial growth factor receptor 1 (P = .003), vascular endothelial growth factor receptor 2 (P = .003), and talin, a microvascular structural protein (P = .0002). There was a slight increase in proteins implicated in endothelial-dependent (nitric oxide mediated) relaxation, including extracellular signal-regulated kinase, phosphorylated extracellular signal-regulated kinase, and inducible nitric oxide synthase with calpain inhibition.
  
  
  CONCLUSIONS
  In the setting of hypercholesterolemia, calpain inhibition improved perfusion, with a trend toward increased collateralization on angiography and increased capillary and arteriolar densities in ischemic myocardium. Calpain inhibition also improved endothelium-dependent microvessel relaxation and increased expression of proteins implicated in angiogenesis and vasodilatation.
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert School of Medicine, Brown University, Providence, RI.
authors.forename: Ashraf A
authors.initials: AA
authors.lastname: Sabe
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert School of Medicine, Brown University, Providence, RI.
authors.forename: Brittany A
authors.initials: BA
authors.lastname: Potz
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert School of Medicine, Brown University, Providence, RI.
authors.forename: Nassrene Y
authors.initials: NY
authors.lastname: Elmadhun
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert School of Medicine, Brown University, Providence, RI.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert School of Medicine, Brown University, Providence, RI.
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert School of Medicine, Brown University, Providence, RI.
authors.forename: M Ruhul
authors.initials: MR
authors.lastname: Abid
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert School of Medicine, Brown University, Providence, RI.
authors.forename: Jinnette D
authors.initials: JD
authors.lastname: Abbott
authors.affiliation: Division of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, Mass.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Senger
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert School of Medicine, Brown University, Providence, RI. Electronic address: fsellke@lifespan.org.
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002908:Chronic Disease; D003097:Collateral Circulation / Q000187:drug effects*; D017023:Coronary Angiography; D003326:Coronary Circulation / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006937:Hypercholesterolemia / Q000150:complications*; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D055806:Microvessels / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D055414:Myocardial Perfusion Imaging; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology*; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects
chemical_list: D042501:Angiogenic Proteins; D011480:Protease Inhibitors; D002154:Calpain
keywords: angiogenesis; animal model surgery; calpain inhibition; collateral circulation; ischemic heart disease; myocardial revascularization; perfusion