A profibrotic effect of plasminogen activator inhibitor type-1 (PAI-1) in the heart.

Abstract

Increased expression of PAI-1 is profibrotic in several organs. However, its potentially profibrotic effects in the heart subjected to infarction have not been elucidated. Accordingly, we induced coronary occlusion in 10-week-old mice congenic on a C57BL6 background and in mice overexpressing PAI-1 (PTG) in multiple tissues. Compared with C57BL6 control mice without myocardial infarction (MI), PTG mice exhibited consistently elevated PAI-1 in plasma at 16 weeks of age but virtually identical PAI-1 content in left ventricular (LV) myocardium. However, they exhibited a 2-fold increase in LV PAI-1 content 6 weeks after induction of MI (4.21 +/- 1.0 ng/ml tissue protein) compared with that in C57BL6 mice (2.04 +/- 0.5, P < 0.05). In 16-week-old mice, ultrasonically delineated LV fractional shortening (FS) was comparable in normal PTG and normal C57BL6 controls. However, 6 weeks after MI, PTG (n = 21) compared with C57BL6 (n = 14) mice exhibited markedly thinner LV posterior walls in both diastole (C57BL6 0.79 +/- 0.05 mm, PTG 0.55 +/- 0.06, P < 0.05) and systole (0.97 +/- 0.05 mm, 0.75 +/- 0.06, P < 0.05); increased end systolic LV dimensions (4.54 +/- 0.2 mm, 5.17 +/- 0.2, P < 0.05); and significantly depressed FS, more impaired LV segmental function, and greater mitral E wave amplitude. Compared with fibrosis assessed by Masson staining of sections from apex to base in C57BL6 mice (10.85 +/- 0.43% LV area), PTG mice exhibited 33% more LV fibrosis after MI (P < 0.05). Thus, PAI-1 is profibrotic in the heart subjected to infarction. Accordingly, overexpression of PAI-1 is a promising target for attenuation of heart failure after MI that may be exacerbated by fibrosis.

• Authors: A K M Tarikuz Zaman, Christopher J French, David J Schneider, Burton E Sobel
• Journal: Experimental biology and medicine (Maywood, N.J.) (Exp Biol Med (Maywood)) Vol. 234 Issue 3 Pg. 246-54 (Mar 2009) ISSN: 1535-3702 [Print] England
• PMID: 19144865 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Plasminogen Activator Inhibitor 1
• Evans Blue
• Creatine Kinase

Topics

• Animals
• Blood Pressure
• Body Weight
• Creatine Kinase (metabolism)
• Echocardiography, Doppler
• Evans Blue
• Fibrosis (pathology, physiopathology)
• Heart Ventricles (diagnostic imaging, enzymology, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Myocardial Infarction (diagnostic imaging, metabolism, pathology, physiopathology)
• Myocardium (metabolism, pathology)
• Organ Size
• Plasminogen Activator Inhibitor 1 (blood, metabolism)
• Ventricular Function, Left