A structural event during the evolution of a myocardial infarction (MI) is left ventricular (LV) remodeling. The mechanisms that contribute to early changes in LV myocardial remodeling in the post-MI period remain poorly understood. Matrix metalloproteinases (MMPs) contribute to tissue remodeling in several disease states. Whether and to what degree MMP activation occurs within the myocardial interstitium after acute MI remains to be determined. Adult pigs (n = 15) were instrumented to measure regional myocardial function and interstitial MMP levels within regions served by the circumflex and left anterior descending arteries. Regional function was measured by sonomicrometry, and interstitial MMP levels were determined by selective microdialysis and zymography as well as by MMP interstitial fluorogenic activity. Measurements were performed at baseline and sequentially for up to 3 h after ligation of the obtuse marginals of the circumflex artery. Regional fractional shortening fell by over 50% in the MI region but remained unchanged in the remote region after coronary occlusion. Release of soluble MMPs, as revealed by zymographic activity of myocardial interstitial samples, increased by 2 h post-MI. The increased zymographic activity after MI was consistent with MMP-9. Myocardial interstitial MMP fluorogenic activity became detectable within the ischemic region as early as 10 min after coronary occlusion and significantly increased after 1 h post-MI. MMP fluorogenic activity remained unchanged from baseline values in the remote region. The present study demonstrated that myocardial MMP activation can occur within the MI region in the absence of reperfusion. These unique results suggest that MMP release and activation occurs within the ischemic myocardial interstitium in the early post-MI period.
Changes in myocardial matrix metalloproteinase (MMP) activity and expression have been associated with left ventricular (LV) remodeling. A recent study demonstrated that LV myocytes synthesize and release MMPs, which suggests that LV myocytes may participate in myocardial remodeling. However, extracellular stimuli that may potentially influence LV myocyte MMP production remains to be defined. In the present study MMP activity and expression were measured in porcine LV myocyte preparations (10(5) total cells; n = 6) following incubation (6 h) with endothelin-1 (ET-1;50 pM), angiotensin II (ANG II; 1 microM), or the beta-receptor agonist isoproterenol (Iso; 10 nM). LV myocyte-conditioned media were then subjected to gelatin zymography and an MMP-2 antibody capture assay. MMP zymographic gelatinase activity and MMP-2 content were increased by over 40% in LV myocyte-conditioned media after incubation with ET-1 or ANG II (P < 0.05). Exposure to the phorbol ester phorbol 12-myristate 13-acetate (PMA; 50 ng/ml) resulted in a 30% increase in zymographic gelatinase activity and a 63% increase in MMP-2 content (P < 0.05), suggesting that protein kinase C activation may be an intracellular mechanism for MMP induction. With the use of a confocal microscopy, membrane type-1 MMP (MT1-MMP) was localized to porcine LV myocytes, and immunoblotting for MT1-MMP using LV myocyte extracts revealed that after exposure to Iso, ET-1, ANG II, or PMA (P < 0.05), MT1-MMP abundance increased over 50%. Thus stimulation of specific neurohormonal systems that are relevant to LV remodeling influences LV myocyte MMP synthesis and release.
Matrix metalloproteinase inhibition reduced postinfarction left ventricular dilation, reduced regional myocardial wall stress, and modified myocardial material properties. These unique findings suggest that increased myocardial matrix metalloproteinase activation after infarction contributes directly to the left ventricular remodeling process.
The present study demonstrated that increased activity of the endothelin-1A receptor likely contributes to alterations in pulmonary vascular resistance in the postbypass setting. Selective endothelin-1A blockade may provide a means to selectively decrease pulmonary vascular resistance without significant effects on systemic hemodynamics.
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