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Arterioscler Thromb Vasc Biol. 2013 Jun;33(6):1339-49. doi: 10.1161/ATVBAHA.113.301533. Epub 2013 Apr 18.

Impaired coronary collateral growth in the metabolic syndrome is in part mediated by matrix metalloproteinase 12-dependent production of endostatin and angiostatin.

Author information

1
Department of Biochemistry and Molecular Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA.

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.

APPROACH AND 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.

KEYWORDS:

angiostatin; coronary collateral growth; endostatin; matrix metalloproteinases

PMID:
23599440
PMCID:
PMC3753795
DOI:
10.1161/ATVBAHA.113.301533
[Indexed for MEDLINE]
Free PMC Article

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