Department of Internal Medicine I, Medical University Innsbruck, Anichstrasse 35, Innsbruck, Austria.
Circulation. 2012 Nov 20;126(21):2491-501. doi: 10.1161/CIRCULATIONAHA.111.076950. Epub 2012 Oct 18.
Secretoneurin is a neuropeptide located in nerve fibers along blood vessels, is upregulated 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.
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 extracellular signal-regulated kinase in coronary endothelial cells. Effects were abrogated by a vascular endothelial growth factor (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 coreceptor neuropilin-1. In endothelial cells, secretoneurin also stimulated fibroblast growth factor receptor-3 and insulin-like growth factor-1 receptor, and in coronary vascular smooth muscle cells, we observed stimulation of VEGF receptor-1 and fibroblast growth factor receptor-3. Exposure of cardiac myocytes to hypoxia and ischemic heart after myocardial infarction revealed increased secretoneurin messenger RNA and protein.
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 fibroblast growth factor receptor-3. Our in vivo findings indicate that secretoneurin may be a promising therapeutic tool in ischemic heart disease.
分泌素是一种位于血管周围神经纤维中的神经肽，可被缺氧上调，并诱导血管生成。我们检验了这样一个假设，即分泌素基因治疗在心肌梗死大鼠模型中发挥有益作用，并评估了其对冠状动脉内皮细胞的作用机制。
在体内，分泌素改善了左心室功能，抑制了重构，并减少了瘢痕形成。在梗塞边缘区，分泌素诱导了冠状动脉血管生成，表现为毛细血管和动脉密度增加。在体外，分泌素诱导了毛细血管管腔形成，刺激了增殖，抑制了凋亡，并激活了冠状动脉内皮细胞中的 Akt 和细胞外信号调节激酶。这些作用被血管内皮生长因子（VEGF）抗体阻断，而分泌素刺激了这些细胞中的 VEGF 受体。分泌素还增加了 VEGF 与内皮细胞的结合，肝素酶阻断了结合，表明分泌素刺激了 VEGF 与硫酸乙酰肝素蛋白聚糖结合位点的结合。此外，分泌素增加了 VEGF 与其核心受体神经纤毛蛋白-1 的结合。在内皮细胞中，分泌素还刺激了成纤维细胞生长因子受体-3 和胰岛素样生长因子-1 受体，在冠状动脉血管平滑肌细胞中，我们观察到 VEGF 受体-1 和成纤维细胞生长因子受体-3 的刺激。心肌细胞暴露于缺氧和心肌梗死后缺血的心脏中，发现分泌素信使 RNA 和蛋白增加。
我们的数据表明，分泌素通过增强 VEGF 与低亲和力结合位点和神经纤毛蛋白-1 的结合，作为冠状动脉内皮细胞中 VEGF 信号的内源性刺激物，刺激进一步的生长因子受体，如成纤维细胞生长因子受体-3。我们的体内发现表明，分泌素可能是缺血性心脏病有前途的治疗工具。
