Myocardial Interstitial Matrix Metalloproteinase Activity Is Altered by Mechanical Changes in LV Load Interaction With the Angiotensin Type 1 Receptor

LV myocardial remodeling is a structural hallmark of hypertensive hypertrophy, but molecular mechanisms driving this process are not well understood. The matrix metalloproteinases (MMPs) can cause myocardial remodeling in chronic disease states, but how MMP activity is altered with a mechanical load remains unknown. The present study quantified interstitial MMP activity after a discrete increase in LV load and dissected out the contributory role of the angiotensin II Type 1 receptor (AT 1 R). Pigs (38kg) were randomized to undergo (1) increased LV load by insertion of an intra-aortic balloon pump (IABP) triggered at systole for 3 hours, then deactivated (n=11); (2) IABP and AT 1 R blockade (AT 1 RB; valsartan, 3 ng/kg/hr; n=6). MMP activity was directly measured in the myocardial interstitium using a validated inline digital fluorogenic microdialysis system. IABP engagement increased LV peak pressure from 92±3 to 113±5 and 123±7 mm Hg in the vehicle and AR 1 RB group, respectively, and remained elevated throughout the IABP period ( P P 1 RB group (2.3±12.5%). MMP activity decreased with IABP in both groups. At IABP disengagement, a surge in MMP activity occurred in the vehicle group that was abrogated with AT 1 RB (3.03±0.85 versus 0.07±1.55 MMP units/hr, P 1 R. These temporally dynamic changes in MMP activity likely influence myocardial function and structure with increased LV load.