Administration of Pigment Epithelium-Derived Factor Inhibits Left Ventricular Remodeling and Improves Cardiac Function in Rats with Acute Myocardial Infarction

Abstract

Oxidative stress and inflammation are involved in cardiac remodeling after acute myocardial infarction (AMI). We have found that pigment epithelium-derived factor (PEDF) inhibits vascular inflammation through its anti-oxidative properties. However, effects of PEDF on cardiac remodeling after AMI remain unknown. We investigated whether PEDF could inhibit left ventricular remodeling and improve cardiac function in rats with AMI. AMI was induced in 8-weekold Sprague-Dawley rats by ligation of the left ascending coronary artery. Rats were treated intravenously with vehicle or 10 g PEDF/100 g b.wt. every day for up to 2 weeks after AMI. Each rat was followed until 16 weeks of age. PEDF levels in infarcted areas and serum were significantly decreased at 1 week after AMI and remained low during the observational periods. PEDF administration inhibited apoptotic cell death and oxidative stress generation around the infarcted areas at 2 and 8 weeks after AMI. Further, PEDF injection suppressed cardiac fibrosis by reducing transforming growth factor-␤ and type III collagen expression, improved left ventricular ejection fraction, ameliorated diastolic dysfunction, and inhibited the increase in left ventricular mass index at 8 weeks after AMI. The present study demonstrated that PEDF could inhibit tissue remodeling and improve cardiac function in AMI rats. Substitution of PEDF may be a novel therapeutic strategy for cardiac remodeling after AMI.

Pigment Epithelium-Derived Factor Regulates Early Pancreatic Fibrotic Responses and Suppresses the Profibrotic Cytokine Thrombospondin-1

“…20 However, in pancreatitis responses, the early fibrosis seen in PEDF-null mice suggests that PEDF serves as a counterregulatory mechanism in pancreatitis. This function is also consistent with recently published data 8,10,18,19 on PEDF's antifibrotic role in the kidney, liver, heart, and eye. PEDF overexpression in a transgenic mouse model ameliorated the increase in TGF-␤1 and inflammatory markers in an eye injury model associated with neovascularization and fibrosis.…”

“…8 Similarly, in a model of acute myocardial infarction, PEDF infusion reduced cardiac fibrosis through down-regulation of TGF-␤1 and fibrillar collagen expression, thereby improving left ventricular ejection. 18 These in vivo studies support earlier cellular studies that identified PEDF as a quiescence factor for fibroblasts.…”

“…8,10,18,19 Pancreatic PEDF expression by mRNA and tissue labeling increased with pancreatitis responses. Ethanol feeding accentuated PEDF labeling, which was most robust in regions of stromal expansion and ductular proliferation.…”

“…MMP-2 levels reflected the relative abundance of gene expression and are consistent with previously published data on PEDF's inhibitory effects on MMP-2 levels and activity in animal models of myocardial infarction. 18 MMP-9 protein levels, however, were lower in PEDF-null mice, indicating the differential regulation of MMP-2 and MMP-9. 32,33 Despite these differences in profibrogenic cytokines, peri-acinar and lobular fibrosis was not visibly greater in PEDF-null mice than in wild-type mice, as determined by Sirius red staining in saline-injected mice (data not shown).…”

“…10 The antifibrogenic properties of PEDF have also been demonstrated in other organs, including the kidney, heart, and eye. 7,8,18,19 PEDF delivery ameliorated kidney fibrosis and proteinuria by suppressing transforming growth factor (TGF)-␤1 expression in diabetic rats. 8 Similarly, in a model of acute myocardial infarction, PEDF infusion reduced cardiac fibrosis through down-regulation of TGF-␤1 and fibrillar collagen expression, thereby improving left ventricular ejection.…”