Matrix metalloproteinase inhibition improves cardiac dysfunction and remodeling in 2-kidney, 1-clip hypertension.
BACKGROUND
Enhanced cardiac matrix metalloproteinase activity (MMPs) has been associated with ventricular remodeling and cardiac dysfunction. It is unknown whether MMPs contribute to systolic/diastolic dysfunction and compensatory remodeling in 2-kidney, 1-clip (2K1C) hypertensive rats. To test this hypothesis, we used 2K1C rats after 2 weeks of surgery treated or not with a nonspecific inhibitor of MMPs (doxycycline).


RESULTS
We found that blood pressure and +/- dP/dt increased in 2K1C rats compared with sham groups, and these parameters were attenuated by doxycycline treatment (P < .05). Doxycycline also reversed cardiac hypertrophy observed in 2K1C rats (P < .05). Hypertensive rats showed increased MMP-2 levels in zymograms and in the tissue by immunofluorescence (P < .05) compared with sham groups. Increased total gelatinolytic activity was observed in untreated 2K1C rats when compared with sham groups (P < .05). Doxycycline decreased total gelatinolytic activity in 2K1C rats to control levels (P < .05).


CONCLUSIONS
An imbalance in gelatinolytic activity, with increased MMP-2 levels and activity underlies the development of morphological and functional alterations found in the compensatory hypertrophy observed in 2K1C hearts. Because function and structure were restored by doxycycline, the inhibition of MMPs or their modulation may provide beneficial effects for therapeutic intervention in cardiac hypertrophy.
Rizzi
Elen
E
Department of Pharmacology, Faculty of Medicine of Ribeirao, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
Castro
Michele M
MM
Prado
Cibele M
CM
Silva
Carlos A
CA
Fazan
Rubens
R
Rossi
Marcos A
MA
Tanus-Santos
Jose E
JE
Gerlach
Raquel Fernanda
RF
D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology*; D004318:Doxycycline / Q000494:pharmacology / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006978:Hypertension, Renovascular / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000502:physiology; D061965:Matrix Metalloproteinase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D013525:Surgical Instruments; D020257:Ventricular Remodeling / Q000502:physiology*
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D004318:Doxycycline