Korean Circulation Journal

  • 제41권10호
  • /
  • Pages.590-595
  • /
  • 2011
  • /
  • 1738-5520(pISSN)
  • /
  • 1738-5555(eISSN)
대한심장학회 (The Korean Society of Cardiology)
권호 표지
DOI QR코드

DOI QR Code

Angiopoietin-1 Gene Therapy Attenuates Hypertension and Target Organ Damage in Nitric Oxide Synthase Inhibited Spontaneously Hypertensive Rats

  • Suh, Won-Hee (College of Pharmacy, Ajou University) ;
  • Lee, Jung-Sun (Department of Medicine, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine) ;
  • Kim, Koung-Li (College of Pharmacy, Ajou University) ;
  • Song, Sun-Hwa (College of Pharmacy, Ajou University) ;
  • Koh, Gou-Young (Biomedical Research Center and Department of Biological Sciences, Korea Advanced Institute of Science and Technology) ;
  • Kim, Duk-Kyung (Department of Medicine, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine)
  • 발행 : 2011.10.30
⟨ 이전 논문 다음 논문 ⟩

초록

Background and Objectives: In our previous study, we found that the gene transfer of a potent derivative of cartilage oligomeric matrix protein Angiopoietin-1 (COMP-Ang-1) substantially prevented hypertension, microvascular rarefaction, and target organ damage in spontaneously hypertensive rats (SHRs). The purpose of the present study was to examine the role of nitric oxide (NO) in the therapeutic effects observed after COMP-Ang-1 gene transfer. Materials and Methods: To exclude the NO-mediated effects in COMP-Ang-1 gene therapy, the SHRs were treated with an NO synthase (NOS) inhibitor, $N^w$-nitro-L-arginine methyl ester (L-NAME) before the electrophoretic gene transfer. Results: The pretreatment with L-NAME induced a severe and sustained increase in systolic blood pressure (BP) in a LacZ plasmid transferred control SHR. However, the electrophoretic transfer of a COMP-Ang-1 plasmid instead of LacZ plasmid in L-NAME-pretreated SHRs substantially blocked the development of hypertension without any significant difference in comparison with L-NAME-untreated COMP-Ang-1 plasmid transferred groups. In addition, the COMP-Ang-1 plasmid transfer substantially attenuated microvascular rarefaction and arteriole remodeling in the heart and kidney, which might account for the mild histological alterations observed in the COMP-Ang-1 plasmid transferred group, in contrast to the severe fibrosis and necrosis seen in the LacZ plasmid controls. Conclusion: These therapeutic outcomes of COMP-Ang-1 gene transfer even in NOS inhibited SHRs suggested that the antihypertensive effect of COMP-Ang-1 was not merely secondary to NO-mediated vasorelaxation, but it may be associated with its ability to protect the vascular endothelium probably via an NO-independent mechanism which serves to attenuate microvascular rarefaction and target organ damage, and also to prevent hypertension by reducing peripheral vascular resistance.

키워드

참고문헌

  1. Cohuet G, Struijker-Boudier H. Mechanisms of target organ damage caused by hypertension: therapeutic potential. Pharmacol Ther 2006;111:81-98. https://doi.org/10.1016/j.pharmthera.2005.09.002
  2. Levy BI, Ambrosio G, Pries AR, Struijker-Boudier HA. Microcirculation in hypertension: a new target for treatment? Circulation 2001;104:735-40. https://doi.org/10.1161/hc3101.091158
  3. Mourad JJ, Laville M. Is hypertension a tissue perfusion disorder? Implications for renal and myocardial perfusion. J Hypertens Suppl 2006;24:S10-6. https://doi.org/10.1097/01.hjh.0000240041.43214.8a
  4. Battegay EJ, de Miguel LS, Petrimpol M, Humar R. Effects of antihypertensive drugs on vessel rarefaction. Curr Opin Pharmacol 2007;7:151-7. https://doi.org/10.1016/j.coph.2006.09.007
  5. Redon J. Antihypertensive treatment: should it be titrated to blood pressure reduction or to target organ damage regression? Curr Opin Nephrol Hypertens 2005;14:448-52. https://doi.org/10.1097/01.mnh.0000168935.95527.0a
  6. Lee JS, Song SH, Kim JM, et al. Angiopoietin-1 prevents hypertension and target organ damage through its interaction with endothelial Tie2 receptor. Cardiovasc Res 2008;78:572-80. https://doi.org/10.1093/cvr/cvn048
  7. Olzinski AR, McCafferty TA, Zhao SQ, et al. Hypertensive target organ damage is attenuated by a p38 MAPK inhibitor: role of systemic blood pressure and endothelial protection. Cardiovasc Res 2005;66:170-8. https://doi.org/10.1016/j.cardiores.2004.12.021
  8. Nakamura Y, Ono H, Zhou X, Frohlich ED. Angiotensin type 1 receptor antagonism and ACE inhibition produce similar renoprotection in N(omega)-nitro-L>-arginine methyl ester/spontaneously hypertensive rats. Hypertension 2001;37:1262-7. https://doi.org/10.1161/01.HYP.37.5.1262
  9. Kubis N, Besnard S, Silvestre JS, et al. Decreased arteriolar density in endothelial nitric oxide synthase knockout mice is due to hypertension, not to the constitutive defect in endothelial nitric oxide synthase enzyme. J Hypertens 2002;20:273-80. https://doi.org/10.1097/00004872-200202000-00017
  10. Kubis N, Richer C, Domergue V, Giudicelli JF, Lévy BI. Role of microvascular rarefaction in the increased arterial pressure in mice lacking for the endothelial nitric oxide synthase gene (eNOS3pt-/- ). J Hypertens 2002;20:1581-7. https://doi.org/10.1097/00004872-200208000-00021
  11. Kim W, Moon SO, Lee SY, et al. COMP-angiopoietin-1 ameliorates renal fibrosis in a unilateral ureteral obstruction model. J Am Soc Nephrol 2006;17:2474-83. https://doi.org/10.1681/ASN.2006020109
  12. Cho CH, Kammerer RA, Lee HJ, et al. Designed angiopoietin-1 variant, COMP-Ang1, protects against radiation-induced endothelial cell apoptosis. Proc Natl Acad Sci U S A 2004;101:5553-8. https://doi.org/10.1073/pnas.0307575101
  13. Cho CH, Sung HK, Kim KT, et al. COMP-angiopoietin-1 promotes wound healing through enhanced angiogenesis, lymphangiogenesis, and blood flow in a diabetic mouse model. Proc Natl Acad Sci U S A 2006;103:4946-51. https://doi.org/10.1073/pnas.0506352103
  14. Kobori H, Ozawa Y, Suzaki YY, Nishiyama A. Enhanced intrarenal angiotensinogen contributes to early renal injury in spontaneously hypertensive rats. J Am Soc Nephrol 2005;16:2073-80. https://doi.org/10.1681/ASN.2004080676
  15. Du WM, Miao CY, Liu JG, Shen FM, Yang XQ, Su DF. Effects of long-term treatment with ketanserin on blood pressure variability and end-organ damage in spontaneously hypertensive rats. J Cardiovasc Pharmacol 2003;41:233-9. https://doi.org/10.1097/00005344-200302000-00012
  16. Noon JP, Walker BR, Webb DJ, et al. Impaired microvascular dilatation and capillary rarefaction in young adults with a predisposition to high blood pressure. J Clin Invest 1997;99:1873-9. https://doi.org/10.1172/JCI119354
  17. Antonios TF, Singer DR, Markandu ND, Mortimer PS, MacGregor GA. Rarefaction of skin capillaries in borderline essential hypertension suggests an early structural abnormality. Hypertension 1999;34: 655-8. https://doi.org/10.1161/01.HYP.34.4.655
  18. Antonios TF, Rattray FM, Singer DR, Markandu ND, Mortimer PS, MacGregor GA. Rarefaction of skin capillaries in normotensive offspring of individuals with essential hypertension. Heart 2003;89:175-8. https://doi.org/10.1136/heart.89.2.175
  19. Jung AD, Kim W, Park SH, et al. The effect of telmisartan on endothelial function and arterial stiffness in patients with essential hypertension. Korean Circ J 2009;39:180-4. https://doi.org/10.4070/kcj.2009.39.5.180

피인용 문헌

  1. Clinical significance of Angiopoietin-1 in Behcet’s disease patients with vascular involvement vol.31, pp.6, 2011, https://doi.org/10.1007/s00380-015-0686-9