title: Impaired coronary collateral growth in the metabolic syndrome is in part mediated by matrix metalloproteinase 12-dependent production of endostatin and angiostatin.
abstract: OBJECTIVE
  We have previously shown that transient coronary artery occlusion stimulated coronary collateral growth (CCG) in healthy (Sprague Dawley) but not in metabolic syndrome (JCR:LA-cp [JCR] ) rats. Here, we sought to determine whether matrix metalloproteinases (MMPs) negatively regulate CCG in the metabolic syndrome via release of endostatin and angiostatin.
  
  
  RESULTS
  Rats underwent transient, repetitive left anterior descending occlusion and resultant myocardial ischemia (RI) for 0 to 10 days. CCG was measured in the collateral-dependent and normal zones using microspheres, MMP activation by Western blot, and endostatin and angiostatin by ELISA on days 0, 3, 6, 9, or 10 of RI. Endostatin and angiostatin were increased in JCR but not in Sprague Dawley rats on days 6 and 9 of RI. Increased endostatin and angiostatin correlated with increased MMP12 (≈ 4-fold) activation in JCR but not in Sprague Dawley rats on days 6 and 9 of RI. Inhibition of MMP12 in JCR rats nearly completely blocked endostatin (≈ 85%) and angiostatin (≈ 90%) generation and significantly improved CCG (collateral-dependent zone flow was ≈ 66% of normal zone flow versus ≈ 12% for JCR RI).
  
  
  CONCLUSIONS
  Compromised CCG in the metabolic syndrome is, in large part, because of increased MMP12 activation and consequent increased generation of endostatin and angiostatin, which inhibits late-stage collateral remodeling.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: Dodd
authors.forename: Luke
authors.initials: L
authors.lastname: Wiggins
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hutcheson
authors.forename: Erika
authors.initials: E
authors.lastname: Smith
authors.forename: Alla
authors.initials: A
authors.lastname: Musiyenko
authors.forename: Brenda
authors.initials: B
authors.lastname: Hysell
authors.forename: James C
authors.initials: JC
authors.lastname: Russell
authors.forename: Petra
authors.initials: P
authors.lastname: Rocic
mesh_terms: D043168:Angiostatins / Q000032:analysis / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D003097:Collateral Circulation / Q000502:physiology*; D003326:Coronary Circulation / Q000502:physiology; D054059:Coronary Occlusion / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D043169:Endostatins / Q000032:analysis / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism*; D024821:Metabolic Syndrome / Q000378:metabolism* / Q000503:physiopathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values
chemical_list: D043169:Endostatins; D043168:Angiostatins; D053508:Matrix Metalloproteinase 12
keywords: angiostatin; coronary collateral growth; endostatin; matrix metalloproteinases