Abstract
Ac-SDKP is an endogenous peptide with anti-inflammation and anti-fibrotic effects in hypertensive and cardiovascular diseases. It is cleaved from Thymosin β4 (Tβ4) and hydrolyzed by angiotensin converting enzyme (ACE). Ac-SDKP plasma concentration increases after treatment with ACE inhibitors (ACEi) and some of the beneficial effects of ACEi treatment has been ascribed to Ac-SDKP. Ac-SDKP is a mediator of angiogenesis in in-vitro and in-vivo animal models. Ac-SDKP stimulates rodents derived immortalized aortic endothelial cells migration and capillary-like structures formation (tube formation). Similarly, Ac-SDKP increases capillary density after myocardial infarction in rats. The mechanism related to angiogenesis induced by Ac-SDKP is not known. Tβ4 (Ac-SDKP precursor) promotes endothelial cell migration and angiogenesis by the activation of the VEGF/AKT pathway. Our objective is to evaluate the Ac-SDKP pro-angiogenic effect in Human Coronary Artery Endothelial Cells (HCAEC) and the mechanism that regulates the angiogenic effect of Ac-SDKP. HCAEC do not produce VEGF, thus we hypothesize that Ac-SDKP increases VEGF expression in fibroblasts and that indirectly could promote capillary tube formation in endothelial cells. We used primary culture of rat cardiac fibroblast (RCF) and we treated these cells with 10nM Ac-SDKP for 24 hours. VEGF concentration in cell supernatant was measured by ELISA. Cells were starved without serum overnight before the Ac-SDKP treatment. For capillary tube formation assay, HCAEC cells were seeded into matrigel and incubated in presence of 10nM Ac-SDKP for 12 hours, pictures were taken by double phase contrast microscope and tube length was quantified with image J software and the results were expressed as percentage of control. After Ac-SDKP treatment, VEGF concentration did not increase in the supernatant of RCF (control: 0.12±0.07 vs. Ac-SDKP: 0.14±0.09 mg/ml; p=0.7). However, Ac-SDKP treatment induced the development of tube formation in HCAECs by 7±2% respect to control (p=0.037). We conclude that Ac-SDKP induces capillary tube formation not only in rodent but also in human derived endothelial cells. The mechanism by which Ac-SDKP promotes tube formation in HCAECs is still unknown.
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