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. METHODS AND 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. CONCLUSION: 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.
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. METHODS AND 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. CONCLUSION: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.
Authors: Anne M Deschamps; Juozas Zavadzkas; Rebecca L Murphy; Christine N Koval; Julie E McLean; Laura Jeffords; Stuart M Saunders; Nina J Sheats; Robert E Stroud; Francis G Spinale Journal: Am J Physiol Heart Circ Physiol Date: 2007-12-07 Impact factor: 4.733