Endogenous angiogenesis inhibitors prevent adaptive capillary growth in left ventricular pressure overload hypertrophy.
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.
Department of Cardiac Surgery, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
Andriana
A
Nikolova
Klemens
K
Ablasser
Moritz C
MC
Wyler von Ballmoos
Dimitrios
D
Poutias
Elisabeth
E
Kaza
Francis X
FX
McGowan
Marsha A
MA
Moses
Pedro J
PJ
Del Nido
Ingeborg
I
Friehs
D043168:Angiostatins / Q000502:physiology; D000818:Animals; D001324:Autoantigens / Q000502:physiology; D024141:Collagen Type IV / Q000502:physiology; D043169:Endostatins / Q000502:physiology; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000503:physiopathology*; D020780:Matrix Metalloproteinase 9 / Q000502:physiology*; D018919:Neovascularization, Physiologic; D011312:Pressure; D011817:Rabbits
D001324:Autoantigens; D024141:Collagen Type IV; D043169:Endostatins; C057112:type IV collagen alpha3 chain; D043168:Angiostatins; D020780:Matrix Metalloproteinase 9