Abstract 18779: sFRP2, Even When Overexpressed in Myocytes, is a Novel Mechanism for Myocardial Ischemic Protection through Angiogenesis
We found that the most upregulated gene induced by delayed ischemic preconditioning of 1 week duration, termed the 3rd window, was “Secreted frizzled related protein 2” (sFRP2). This gene was not upregulated in traditional 1st or 2nd window preconditioning, suggesting that sFRP2 is a novel mediator of cardiac protection conferred by chronic ischemia, as occurs in patients with coronary disease. Accordingly, we developed a transgenic (TG) mouse with cardiac myocyte specific sFRP2 overexpression and examined the effects of permanent coronary artery occlusion (CAO). WT and TG mice (n=10/group), with no differences in baseline cardiac function, were subjected to complete CAO for 4 wks. After 4 wks CAO, the sFRP2 TG mice, compared to WT, showed improved left ventricular (LV) function as reflected by increased LV ejection fraction (EF) (64±2% vs. 46±8%, p<0.05), reduced scar size (9±1% vs. 20±3% p<0.05), and reduced fibrosis in the adjacent zone (16±2% vs. 24±3% p<0.05). We hypothesized that the protection was mediated by angiogenesis or arteriogenesis, since these are the only mechanisms to induce cardiac protection in the face of permanent CAO. The hypothesis was confirmed by demonstrating increased angiogenesis, using isolectin/Ki67 staining (9±3 vs. 6±2 positive cells/field, p<0.05). This was surprising, since the sFRP2 gene was overexpressed only in myocytes. To determine if sFRP2 in myocytes could induce angiogenesis, we isolated rat neonatal myocytes and infected them with either sFRP2 protein, vehicle, sFRP2 adenovirus or ß-gal adenovirus. Myocyte culture medium was collected 24 hours after infection and added to the culture medium of Human Umbilical Vein Endothelial Cells (HUVEC). The medium from sFRP2 protein and adenovirus treated myocytes exhibited significant increases in vascular tube formation in HUVEC by 27 % and 12 % respectively (p<0.05 vs. WT) compared with vehicle and control ß-gal adenovirus. This activation of angiogenesis was abolished in the presence of Sunitinib, an inhibitor of vascular growth factor receptor. Thus, sFRP2, even when overexpressed in myocytes, is a novel mechanism for induction of angiogenesis and consequent protection against chronic myocardial ischemia induced by permanent CAO.
Author Disclosures: X. Sui: None. L. Yan: None. S. Vatner: None. D. Vatner: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.