1. Angiopoietin-1 prevents hypertension and target organ damage through its interaction with endothelial Tie2 receptor
- Author
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Koung Li Kim, Duk-Kyung Kim, Hak-Zoo Kim, Wonhee Suh, Jung-Sun Lee, Eun-Seok Jeon, Sun-Hwa Song, Yeon-Lim Suh, In-Soon Shin, Gou Young Koh, Jeong-Min Kim, and Jonghoe Byun
- Subjects
Male ,Physiology ,Electrochemotherapy ,Nitric Oxide Synthase Type II ,Blood Pressure ,Rats, Inbred WKY ,chemistry.chemical_compound ,Rats, Inbred SHR ,Endothelial dysfunction ,Receptor ,Kidney ,Gene Transfer Techniques ,Angiopoietin receptor ,Receptor, TIE-2 ,medicine.anatomical_structure ,Hypertension ,cardiovascular system ,Rarefaction ,Disease Progression ,Kidney Diseases ,Cardiology and Cardiovascular Medicine ,medicine.medical_specialty ,Endothelium ,Heart Diseases ,Nitric Oxide Synthase Type III ,Recombinant Fusion Proteins ,Biology ,Nitric oxide ,Physiology (medical) ,Internal medicine ,medicine ,Angiopoietin-1 ,Animals ,Antihypertensive Agents ,Nitrites ,Cartilage oligomeric matrix protein ,Target organ damage ,Original Articles ,Genetic Therapy ,medicine.disease ,Capillaries ,Rats ,Enzyme Activation ,Disease Models, Animal ,Blood pressure ,Endocrinology ,chemistry ,biology.protein ,Endothelium, Vascular - Abstract
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.
- Published
- 2008