Angiopoietin-1 prevents hypertension and target organ damage through its interaction with endothelial Tie2 receptor.
OBJECTIVE
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.


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.


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 BP.
Lee
Jung-Sun
JS
Department of Medicine, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-ku, Seoul 135-710, Korea.
Song
Sun-Hwa
SH
Kim
Jeong-Min
JM
Shin
In-Soon
IS
Kim
Koung Li
KL
Suh
Yeon-Lim
YL
Kim
Hak-Zoo
HZ
Koh
Gou Young
GY
Byun
Jonghoe
J
Jeon
Eun-Seok
ES
Suh
Wonhee
W
Kim
Duk-Kyung
DK
D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism*; D001794:Blood Pressure; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D053672:Electrochemotherapy; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006331:Heart Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D006973:Hypertension / Q000150:complications / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000097:blood; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D042787:Receptor, TIE-2 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*
D042683:Angiopoietin-1; D000959:Antihypertensive Agents; C515576:COMP-Ang1 fusion protein; D009573:Nitrites; D011993:Recombinant Fusion Proteins; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D042787:Receptor, TIE-2