Cardiovascular Research Advance Access [Accepted Manuscript] published online on February 19, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn048
Angiopoietin-1 Prevents Hypertension and Target Organ Damage Through its Interaction with Endothelial Tie2 Receptor
1 Department of Medicine, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-ku, Seoul, KOREA
2 Department of Molecular and Life Science, Pochon CHA University, Seoul, KOREA
3 Department of Pathology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-ku, Seoul, KOREA
4 Biomedical Research Center and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, KOREA
5 Department of Molecular Biology, BK21 Graduate Program for RNA Biology, Institute of Nanosensor and Biotechnology, Dankok University, Seoul, KOREA
Corresponding authors: Duk-Kyung Kim, MD, PhD Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-ku, Seoul 135-710, KOREA Tel: 82-2-3410-3419, FAX: 82-2-3410-3849, E-mail: dkkim{at}skku.edu
Wonhee Suh, PhD Department of Molecular and Life Science, Pochon CHA University, CHA Stem Cell Institute, Yeoksam1-dong, Kangnam-ku, Seoul 135-907, KOREA Tel: 82-2-3468-3668, FAX: 82-2-3468-3373, E-mail: wsuh{at}cha.ac.kr
Aims: The endothelium has emerged recently as a therapeutic target in the treatment of hypertension because endothelial dysfunction and subsequent vascular rarefaction causes target organ damage and further elevates blood pressure. It led us to hypothesize that one of the endothelial survival factors, a potent derivative of angiopoietin-1 (COMP-Ang-1), could be a novel class of antihypertensive agents that maintain endothelial integrity and function, thereby preventing the development of hypertension and target organ damage.
Methods and Results: To study the role of COMP-Ang-1 in preventing hypertension and target organ damage, a COMP-Ang-1 plasmid was electroporated into adductor muscles of six-week old, prehypertensive spontaneously hypertensive rats (SHR), and the secretion of its expressed protein into the bloodstream was confirmed by Western blotting. In comparison with sham and reporter gene transfer, COMP-Ang-1 gene transfer significantly prevented increases in systolic blood pressure and reduced microvascular rarefaction and tissue damage in the heart and kidney. However, overexpression of soluble Tie2 receptor completely abolished these beneficial effects of COMP-Ang-1 gene transfer on SHR, indicating that expressed COMP-Ang-1 protein has antihypertensive effects in SHR by binding Tie2 receptors on the vascular endothelium. In particular, COMP-Ang-1 gene-transferred SHR had significantly higher plasma levels of nitrite than other controls, which was found to be due to expressed COMP-Ang-1 protein promoting nitrite synthesis by activating endothelial nitric oxide synthase (eNOS), one of the Tie2 downstream signaling molecules.
Conclusions: The present study suggests a new potential of endothelial survival factor, COMP-Ang-1, as an antihypertensive agent that effectively reduces the hypertension-associated cardiovascular and renal damage as well as prevents the further elevation of blood pressure.
KEYWORDS angiopoietin-1; endothelium; hypertension; nitric oxide; rarefaction; target organ damage
Time for primary review: 23 days
6 These corresponding authors equally contributed to this work.
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