Improved balance between TIMP-3 and MMP-9 after regional myocardial ischemia-reperfusion during AT1 receptor blockade.
BACKGROUND
Angiotensin II (AngII) modulates the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs), and AngII type 1 receptor (AT1R) blockers (ARBs) limit left ventricular (LV) dysfunction and remodeling after acute ischemia-reperfusion (IR). Whether ARBs improve TIMP/MMP balance during IR has not been determined.


RESULTS
We measured hemodynamics, LV function, MMP-2 and MMP-9, and TIMP-3 and TIMP-4 in the ischemic zone (IZ) and nonischemic zone (NIZ) after in vivo IR (90 minutes anterior ischemia; 120 minutes reperfusion) in 28 dogs that were randomized to sham, IR controls, and IR plus the ARB valsartan. In controls, IR induced LV dysfunction, infarction, and IZ remodeling; increased MMP-9 and decreased TIMP-3 in the IZ compared with the NIZ (low TIMP-3/MMP-9 ratio); and did not change MMP-2 or TIMP-4. Compared with controls, valsartan (1) limited LV dysfunction, infarct size, and IZ remodeling; (2) increased MMP-2 and MMP-9 and TIMP-3 and -4 in the NIZ; and (3) increased TIMP-3 and the TIMP-3/MMP-9 ratio in the IZ, but did not change MMP-2 and TIMP-4.


CONCLUSIONS
Valsartan-induced cardioprotection after IR is associated with enhanced TIMP-3 expression and improved TIMP-3/MMP-9 balance in the in vivo dog model.
Cardiovascular Research Group, Division of Cardiology, University of Alberta, Edmonton, Canada.
Grzegorz
G
Sawicki
Vijayan
V
Menon
Bodh I
BI
Jugdutt
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D003720:Densitometry; D004195:Disease Models, Animal; D004285:Dogs; D004562:Electrocardiography; D015180:Electrophoresis, Gel, Two-Dimensional; D006339:Heart Rate / Q000187:drug effects; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D015425:Myocardial Reperfusion; D011897:Random Allocation; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism*; D016896:Treatment Outcome; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000068756:Valsartan; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000378:metabolism*
D047228:Angiotensin II Type 1 Receptor Blockers; D013777:Tetrazoles; D019717:Tissue Inhibitor of Metalloproteinase-3; D000068756:Valsartan; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D014633:Valine