Gelatinase B(MMP-9) an apoptotic factor in diabetic transgenic mice.
OBJECTIVE
Although matrix metalloproteinase-9 (MMP-9) is specifically induced and apoptosis of endothelial cells is evidenced in diabetes mellitus, the mechanism of endocardial endothelial dysfunction in diabetes mellitus is not clear. The increase in MMP-9 activity is associated with endocardial endothelial apoptosis and dysfunction in diabetes mellitus.


METHODS
Diabetes was created by injecting 65 mg/kg alloxan in tail vein of MMP-9 knockout (-/-) and wild-type (WT, C57BL/J6) mice. At 8 weeks mice were grouped: (i) WT+saline; (ii) WT+alloxan; (iii) MMP+saline; (iv) MMP+alloxan. The MMP-9 genotype was determined by observing single PCR product of different mobility than the PCR product from wild-type in blood from tail vein.


RESULTS
MMP-9 activity, measured by zymography, increased in plasma and in the left ventricle of alloxan-induced diabetic wild-type mice. The concentrations of cardiac inhibitor of metalloproteinase, that blocks MMP-9 activity, were decreased in diabetic MMP-9 knockouts as well as in wild-type mice. Diabetes induced apoptosis, detected by TUNEL assays, in wild-type but not in MMP-9 knockouts. Endocardial endothelial function was severely impaired in diabetic wild-type mice compared with normoglycaemic animals, while non-diabetic MMP-9 knockout mice showed partial endocardial endothelial dysfunction which was not further exacerbated by the developments of diabetes.


CONCLUSIONS
The results suggest an association between increased MMP-9 activity and endocardial endothelial apoptosis in diabetic mice, while genetic ablation of MMP-9 correlated with amelioration of endocardial endothelial dysfunction and apoptosis.
Camp
T M
TM
Department of Physiology and Biophysics, University of Louisville, 500 South Preston Street, Louisville, KY 40292, USA.
Tyagi
S C
SC
Senior
R M
RM
Hayden
M R
MR
Tyagi
S C
SC
D000818:Animals; D017209:Apoptosis; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004699:Endocardium / Q000473:pathology / Q000503:physiopathology; D042783:Endothelial Cells; D005109:Extracellular Matrix / Q000378:metabolism; D006439:Hemodynamics; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout
D003094:Collagen; D020780:Matrix Metalloproteinase 9