Document Detail

Endogenous angiogenesis inhibitors prevent adaptive capillary growth in left ventricular pressure overload hypertrophy.
MedLine Citation:
PMID:  22795062     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: In left ventricular (LV) pressure-overload hypertrophy, lack of adaptive capillary growth contributes to progression to failure. Remodeling of the hypertrophied myocardium requires proteolysis of the extracellular matrix (ECM) carried out by matrix metalloproteinases (MMPs). MMPs, specifically MMP-9, are known to cleave ECM components to generate angiogenesis inhibitors (angiostatin, endostatin, tumstatin). We hypothesize that MMP-9 releases antiangiogenic factors during compensated and decompensated hypertrophy, which results in lack of adaptive capillary growth.
METHODS: Newborn rabbits underwent aortic banding. Myocardial tissue from age-matched and banded animals at compensated (4 weeks) and decompensated hypertrophy (7 weeks), as identified by serial echocardiography, was analyzed by immunoblotting for angiostatin, endostatin, and tumstatin. MMP-9 activity was determined by zymography. A cell-permeable, potent, selective MMP-9 inhibitor was administered intrapericardially to animals with hypertrophied hearts and tissue was analyzed.
RESULTS: MMP-9 is activated in hypertrophied myocardium versus in control hearts (22 ± 2 versus 16 ± 1; p = 0.04), which results in significantly increased levels of angiostatin (115 ± 10 versus 86 ± 7; p = 0.02), endostatin (33 ± 1 versus 28 ± 1; p = 0.006), and tumstatin (35 ± 6 versus 17 ± 4; p = 0.04). Zymography confirms inhibition of MMP-9 (hypertrophy + MMP-9 inhibitor, 14 ± 0.6 versus hypertrophy + vehicle, 17 ± 1; p = 0.01) and angiostatin, endostatin, and tumstatin are down-regulated, accompanied by up-regulation of capillary density (hypertrophy + MMP-9 inhibitor, 2.99 ± 0.07 versus hypertrophy + vehicle, 2.7 ± 0.05; p = 0.002).
CONCLUSIONS: Up-regulation of angiogenesis inhibitors prevents adaptive capillary growth in pressure-overload hypertrophied myocardium. Therapeutic interventions aimed at inhibition of angiogenesis inhibitors are useful in maintaining capillary density and thereby preventing heart failure.
Andriana Nikolova; Klemens Ablasser; Moritz C Wyler von Ballmoos; Dimitrios Poutias; Elisabeth Kaza; Francis X McGowan; Marsha A Moses; Pedro J Del Nido; Ingeborg Friehs
Publication Detail:
Type:  Journal Article     Date:  2012-07-12
Journal Detail:
Title:  The Annals of thoracic surgery     Volume:  94     ISSN:  1552-6259     ISO Abbreviation:  Ann. Thorac. Surg.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-26     Completed Date:  2013-01-07     Revised Date:  2013-11-06    
Medline Journal Info:
Nlm Unique ID:  15030100R     Medline TA:  Ann Thorac Surg     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  1509-17     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.
Department of Cardiac Surgery, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
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MeSH Terms
Angiostatins / physiology
Autoantigens / physiology
Collagen Type IV / physiology
Endostatins / physiology
Hypertrophy, Left Ventricular / enzymology,  physiopathology*
Matrix Metalloproteinase 9 / physiology*
Neovascularization, Physiologic*
Grant Support
Reg. No./Substance:
0/Autoantigens; 0/Collagen Type IV; 0/Endostatins; 0/type IV collagen alpha3 chain; 86090-08-6/Angiostatins; EC Metalloproteinase 9
Comment In:
Ann Thorac Surg. 2012 Nov;94(5):1517-8   [PMID:  23098933 ]

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