Cardiovascular Research Advance Access first published online on February 19, 2008
This version [Corrected Proof] published online on March 30, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn048
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Angiopoietin-1 prevents hypertension and target organ damage through its interaction with endothelial Tie2 receptor
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1 Department of Medicine, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-ku, Seoul 135-710, Korea
2 Department of Molecular and Life Science, CHA Stem Cell Institute, Pochon CHA University, Yeoksam1-dong, Kangnam-ku, Seoul 135-907, Korea
3 Department of Pathology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-ku, Seoul 135-710, Korea
4 Biomedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon, Korea
5 Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea
6 BK21 Graduate Program for RNA Biology, Department of Molecular Biology, Institute of Nanosensor and Biotechnology, Dankok University, Seoul, Korea
* Corresponding authors. Tel: +82 2 3410 3419; fax: +82 2 3410 3849. E-mail address: dkkim{at}skku.edu (D.-K.K.); Tel: +82 2 3468 3668; fax: +82 2 3468 3373. E-mail address: wsuh{at}cha.ac.kr (W.S.)
Aims: The endothelium has emerged recently as a therapeutic target in the treatment of hypertension because endothelial dysfunction and subsequent vascular rarefaction cause target organ damage and further elevate blood pressure (BP). It led us to hypothesize that one of the endothelial survival factors, a potent derivative of angiopoietin-1 (cartilage oligomeric matrix protein, 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 6 weeks old, pre-hypertensive, spontaneously hypertensive rats (SHRs), 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 BP 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 SHRs, indicating that expressed COMP-Ang-1 protein has antihypertensive effects in SHRs by binding Tie2 receptors on the vascular endothelium. In particular, COMP-Ang-1 gene-transferred SHRs had significantly higher plasma levels of nitrite than other controls, which was found to be due to that expressed COMP-Ang-1 protein promoted nitrite synthesis by activating endothelial nitric oxide synthase, one of the Tie2 downstream-signalling molecules.
Conclusion: 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 BP.
KEYWORDS Angiopoietin-1; Endothelium; Hypertension; Nitric oxide; Rarefaction; Target organ damage
Time for primary review: 23 days
These authors contributed equally to this work.
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