Abstract 13861: Overexpression of Plasminogen Activator Inhibitor-1 Ameliorates Cardiac Rupture after Experimental Myocardial Infarction in PAI-1 Transgenic Mice via Inhibiting Inflammatory Cell Accumulation and MMPs Activity
Background: Left ventricular (LV) remodeling after myocardial infarction (MI) leads to congestive heart failure and sudden cardiac death. Ischemic injury and the inflammatory response involved in this maladaptive process may also contribute to cardiac rupture. Plasminogen activator inhibitor-1(PAI-1) plays a critical role in cardiac fibrosis. However little is known about the role of the plasminogen-plasmin system in cardiac rupture. We assessed the hypothesis that PAI-1 overexpression in the heart inhibits MMPs activity and reduces cardiac rupture after MI by using PAI-1 transgenic (TG) mice.
Methods: We have developed TG mice which overexpress PAI-1 in vascular endothelial cells virtually exclusively. The TG mice were generated with expression of human PAI-1 driven by murine endothelin promoter. MI was induced by coronary artery occlusion in 12 to 16 weeks old PAI-1 TG mice and wild-type (WT) mice. Hearts were harvested at 0, 2, 4, 7 and 28 days after MI. LV function was assessed with echocardiography and infarct area was determined histologically and inflammatory cell accumulation in infarct area was characterized by immunocytochemistry. Gelatin zymography was performed to analyze activated MMP-2 and MMP-9 at each day.
Results: As compared with WT mice, the rate of cardiac rupture during 28 days of follow-up was significantly lower in PAI-1 TG mice (WT 24.2% vs. TG 11.7%, n=34, P<0.05). PAI-1 TG mice had smaller left ventricular end-diastolic diameter at 28 days after MI (WT 5.15 ± 0.68 mm vs. TG 4.31 ± 0.27 mm, P<0.05). Global cardiac function was lower in WT mice (WT 11% vs. TG 17%, % fractional shortening). Infarction size was smaller in PAI-1 TG mice than WT mice (P<0.05). PAI-1 TG mice had significantly lower neutrophilic infiltration (CD45 positive cells) at 4 days (P<0.05) and macrophage accumulation (Mac-3 positive cells) at 4 to 7 days after MI (P<0.01). MMP-9 activity was significantly lower at 4 days (P<0.01) and MMP-2 activity was significantly lower at 4 to 7 days after MI in PAI-1 TG mice (P<0.05).
Conclusions: PAI-1 overexpression in the heart ameliorates cardiac rupture after MI in PAI-1 TG mice via inhibiting inflammatory cell accumulation and MMPs activity.
- © 2012 by American Heart Association, Inc.