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(Circulation Research. 2005;96:1110.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Myocardial Interstitial Matrix Metalloproteinase Activity Is Altered by Mechanical Changes in LV Load

Interaction With the Angiotensin Type 1 Receptor

Anne M. Deschamps^*, Kimberly A. Apple^*, Amy H. Leonardi, Julie E. McLean, William M. Yarbrough, Robert E. Stroud, Leslie L. Clark, Jeffrey A. Sample, Francis G. Spinale

From the Division of Cardiothoracic Surgery (A.M.D., K.A.A., A.H.L., J.E.M., W.M.Y., R.E.S., J.A.S., F.G.S.), Department of Biostatistics, Bioinformatics and Epidemiology (L.L.C.), Medical University of South Carolina, Charleston, SC, The Ralph H. Johnson Veteran’s Affairs Medical Center

Correspondence to Dr Francis G. Spinale, Cardiothoracic Surgery, Strom Thurmond Research Building, 114 Doughty Street, Room 625, Medical University of South Carolina, Charleston, SC 29403.

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 (AT₁R). 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 AT₁R blockade (AT₁RB; 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 AR₁RB group, respectively, and remained elevated throughout the IABP period (P<0.05). With IABP disengagement, segmental shortening (% change from baseline of 0) remained depressed in the vehicle group (-32.2±11.8%, P<0.05) but returned to baseline in the AT₁RB 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 AT₁RB (3.03±0.85 versus 0.07±1.55 MMP units/hr, P<0.05). A transient increase in LV load caused a cyclic variation in interstitial MMP activity that is regulated in part by the AT₁R. These temporally dynamic changes in MMP activity likely influence myocardial function and structure with increased LV load.

Key Words: matrix metalloproteinase • extracellular matrix • angiotensin II type I receptor

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