The Angiogenic Factor Secretoneurin Induces Coronary Angiogenesis in a Model of Myocardial Infarction by Stimulation of Vascular Endothelial Growth Factor Signaling in Endothelial Cells

Abstract

Background Secretoneurin is a neuropeptide located in nerve fibers along blood vessels, is up-regulated by hypoxia and induces angiogenesis. We tested the hypothesis that secretoneurin gene therapy exerts beneficial effects in a rat model of myocardial infarction and evaluated the mechanism of action on coronary endothelial cells. Methods and Results In-vivo secretoneurin improved left ventricular function, inhibited remodeling and reduced scar formation. In the infarct border zone secretoneurin induced coronary angiogenesis as shown by increased density of capillaries and arteries. In-vitro secretoneurin induced capillary tubes, stimulated proliferation, inhibited apoptosis and activated Akt and ERK in coronary endothelial cells. Effects were abrogated by a VEGF-antibody and secretoneurin stimulated VEGF receptors in these cells. Secretoneurin furthermore increased binding of VEGF to endothelial cells and binding was blocked by heparinase indicating that secretoneurin stimulates binding of VEGF to heparan sulfate proteoglycan binding sites. Additionally, secretoneurin increased binding of VEGF to its co-receptor neuropilin 1. In endothelial cells secretoneurin also stimulated FGF receptor-3 and IGF-1 receptor and in coronary vascular smooth muscle cells we observed stimulation of VEGF receptor-1 and FGF receptor-3. Exposure of cardiac myocytes to hypoxia and ischemic heart after myocardial infarction revealed increased secretoneurin m-RNA and protein. Conclusions Our data show that secretoneurin acts as an endogenous stimulator of VEGF signaling in coronary endothelial cells by enhancing binding of VEGF to low affinity binding sites and neuropilin 1 and stimulates further growth factor receptors like FGF receptor-3. Our in-vivo findings indicate that secretoneurin might be a promising therapeutic tool in ischemic heart disease.

Integrated Bioinformatics Analysis Predicts the Key Genes Involved in Aortic Valve Calcification: From Hemodynamic Changes to Extracellular Remodeling

“…SCG2 was significantly up-regulated in calcific valves and was predicted to be a CAVD-related gene by WGCNA. Cleavage of SCG2 produces the active peptide secretoneurin, which could induce coronary angiogenesis in myocardial infarction by enhancing VEGF signaling in endothelial cells (Albrecht-Schgoer et al 2012). As angiogenesis may contribute to CAVD progression (Weiss et al 2013), it is necessary to ascertain the exact role of SCG2 in CAVD etiology.…”

Prognostic Value of Secretoneurin in Critically Ill Patients With Infections

“…Hence, secretoneurin seems to provide incremental prognostic information to established risk indices in patients with CVD, although not being an unspecific biomarker of disease severity per se. This model is supported by the direct inhibitory effect by secretoneurin on diastolic Ca 2+ leak via Ca 2+ /calmodulin-dependent protein kinase II δ inhibition (9) and reduced cardiomyocyte apoptosis and myocardial ischemia/reperfusion injury by secretoneurin in experimental models (11,12). Accordingly, as cardiovascular, renal, and neuroendocrine system dysfunctions influence outcome in patients with severe infections (1), we hypothesized that secretoneurin would provide important prognostic information in critically ill patients with infections.…”

Alcohol Consumption Negates Estrogen-mediated Myocardial Repair in Ovariectomized Mice by Inhibiting Endothelial Progenitor Cell Mobilization and Function

“…Harvest of Cardiac Tissue, Histology, and Immunofluorescent Assessments-All hearts were harvested after the 28-day echocardiographic analysis as described previously (25,26), embedded in paraffin, and cut into sections for immunohistochemical staining as described previously (22)(23)(24)27). Specimens were fixed in 10% (v/v) buffered formaldehyde, dehydrated with graded ethanol series, and embedded in paraffin.…”