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Effects of L-Arginine Supplementation and Regular Exercise in D-Galactose Induced Aging Rat Aorta: Study on Inflammatory Factors, Vasodilation Regulatory Factors

노화유도 쥐의 대동맥에서 L-arginine 투여와 규칙적인 운동의 효과: 염증인자와 혈관이완조절 인자의 변화

  • Lee, Jin (Department of Anatomy and Cell Biology, Collage of Medicine, Han-Yang University) ;
  • Kwak, Yi-Sub (Department of Physical Education, Dong Eui University) ;
  • Yoo, Young-June (Department of Physical Education, Sejong University) ;
  • Park, Sok (Department of Physiology, Collage of Medicine, Aju University)
  • 이진 (한양대학교 의과대학 해부세포생물학교실) ;
  • 곽이섭 (동의대학교 체육학과) ;
  • 유영준 (세종대학교 체육학과) ;
  • 박석 (아주대학교 의과대학 생리학교실)
  • Received : 2011.07.09
  • Accepted : 2011.09.23
  • Published : 2011.10.31

Abstract

The purpose of this study was to identify the effects of an L-arginine supplementation and regular exercise training on NF-${\kappa}B$, TNF-${\alpha}$, iNOS, Cav-1, eNOS and Ang II in the aortas of D-galactose (D-gal) induced aging rats. The male Strague-Dawley rats were treated with a D-galactose aging inducing agent; the D-gal injection (50 mg/kg) was given intraperitoneally for 12 wk. Experimental groups were divided into five groups: (1) Young control group (Y-Con, n=8), (2) Aging control group (A-Con, n=8), (3) Aging exercise group (A-Ex, n=8), (4) Aging exercise group with L-arginine supplementation group (A-Ex+A, n=8), and (5) Aging with L-arginine supplementation group (A-A, n=8). The exercise consisted of running on a treadmill for 60 min/day at 20 m/min for 6 day/wk, at 0% gradient for 12 wk. The L-arginine supplementation was given orally at a dose of 150 mg/kg/day for 12 wk. The findings of this study were as follows: 1. NF-${\kappa}B$, TNF-${\alpha}$, iNOS, Cav-1 and Ang II proteins in the aortas of D-gal induced rats were significantly increased, however, L-arginine supplementation and regular exercise resulted in a significant inhibition in the expression of NF-${\kappa}B$, TNF-${\alpha}$, iNOS, Cav-1 and Ang II proteins. 2. eNOS protein in the aortas of D-gal induced rats was significantly decreased, however, L-arginine supplementation and regular exercise resulted in a significant increase in the expression of eNOS proteins. In conclusion, the findings of the present study reveal that L-arginine supplementation alone or regular exercise alone or in combination with L-arginine supplementation for 12 wk increases anti-inflammatory effects by decreasing NF-${\kappa}B$, TNF-${\alpha}$, and iNOS protein expressions within the aortic tissue. In addition, L-arginine supplementation alone or regular exercise alone or in combination with L-arginine supplementation may prevent endothelial function by up-regulation of eNOS protein in the aortas of D-gal induced aging rats.

이 연구는 L-arginine과 규칙적인 운동이 D-galctose (D-all)투여로 유발된 노화흰쥐의 대동맥에서 발현되는 NF-${\kappa}B$, TNF-a, iNOS, Cav-1, eNOS, Ang II의 변화양상을 관찰하는데 그 목적을 두고 있다. 노화유도 모델 쥐는 D-gal (50 mg/kg)를 숫컷 Strague-Dawley (SD)계 흰쥐의 복강에 1일 1회 총 12주간 투여하여 생산하였으며, 이 실험의 집단은 젊은 대조군(Y-con, n=8), 노화 대조군(A-con, n=8), 노화 운동군(A-Ex, n=8), 노화운동+아르기닌군(A-Ex+A, n=8), 노화 아르기닌군(A-A, n=8)의 5군으로 분류하여 실시하였다. L-arginine은 1일 150 mg/kg씩 총 12주간 경구투여 하였다. 운동방법은 트레이드운동으로 1일 60분씩 20 m/min 속도에서 훈련하였다. 분석결과 1) 유도된 노화군에서 NF-${\kappa}B$, TNF-a, iNOS, Cav-1, 그리고 Ang II 단백질의 발현은 젊은 대조군에 비해 유의하게 증가하였다. 그러나 규칙적인 운동과 L-아르기닌군에서 NF-${\kappa}B$, TNF-a, iNOS, Cav-1, 그리고 Ang II 단백질의 발현은 노화 대조군에 비해 유의하게 감소하였다. 2) 유도된 노화군에서의 eNOS 단백질 발현은 젊은 대조군에 비해 유의하게 감소하였다. 그러나 규칙적인 운동과 L-아르기닌군은 eNOS 단백질의 발현을 더욱 증가시킨 것으로 나타났다. 이상의 결과를 종합하면 12주간 L-아르기닌 투여와 규칙적인 운동 그리고 복합처치는 염증인자와 관련된 단백질인 NF-${\kappa}B$, TNF-a, iNOS 단백질들의 발현을 억제시켜 항염증효과를 보여주었으며, 혈관내피의 기능향상과 관련된 eNOS의 발현을 증가시키는데 긍정적인 역할을 수행할 것으로 기대된다.

Keywords

References

  1. Adriao, M., C. J. Chrisman, M. Bielavsky, S. C. Olinto, E. M. Shiraishi, and M. T. Nunes. 2004. Arginine increases growth hormone gene expression in rat pituitary and GH3 cells. Neuroendocrinology 79, 26-33. https://doi.org/10.1159/000076043
  2. Boger, R. H. and S. M. Bode-Boger. 2001. The clinical pharmacology of L-arginine. Annu. Rev. Pharmacol. Toxicol. 41, 79-99. https://doi.org/10.1146/annurev.pharmtox.41.1.79
  3. Braunwald, E. 1997. Shattuck lecture-Cardiovascular medicine at the turn of the millenium: triumphs, concerns, and opportunities. N. Engl. J. Med. 337, 1360-1369. https://doi.org/10.1056/NEJM199711063371906
  4. Brod, S. A. 2000. Unreulated inflammation shortens human functional longevity. Inflamm Res. 49, 561-570. https://doi.org/10.1007/s000110050632
  5. Bradford, M. M. 1976. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72, 248-254. https://doi.org/10.1016/0003-2697(76)90527-3
  6. Carman, C. V., M. P. Lisanti, and J. L. Benovic. 1999. Regulation of G protein-coupled receptor kinases by caveolin. J. Biol. Chem. 274, 8858-8864. https://doi.org/10.1074/jbc.274.13.8858
  7. Cho, K. A., S. J. Ryu, J. S. Park, I. S., Jang, J. S. Ahn, K. T. Kim, and S. C. Park. 2003. Senescent phenotype can be reversed by reduction of caveolin status. J. Biol. Chem. 278, 27789-27795. https://doi.org/10.1074/jbc.M208105200
  8. Chung, H. Y., H. J. Kim, K. W. Kim, J. S. Choi, and B. P. Yu. 2002. Molecular inflammation hypothesis of aging based on the anti-aging mechanism of calorie restriction. Microsc. Res. Tech. 59, 264-272. https://doi.org/10.1002/jemt.10203
  9. Chang, S. P., Y. H. Chen, W. C. Chang, I. M. Liu, and J. T. Cheng. 2004. Increase of anti-oxidation by exercise in the liver of obese Zucker rats. Clin. Exp. Pharmacol. Physiol. 31, 506-511. https://doi.org/10.1111/j.1440-1681.2004.04035.x
  10. Chung, H. Y., B. Sung, K. J. Jung, Y. Zou, and B. P. Yu. 2006. The molecular inflammatory process in aging. Antioxid. Redox. Signal. 8, 572-581. https://doi.org/10.1089/ars.2006.8.572
  11. Chung, H. Y., M. Cesari, S. Anton, E. Maezetti, S. Giovannini, A. Y. Seo, C. Carter, B. P. Tu, and C. Leeuwenburgh. 2009. Molecular inflammation: underpinnings of aging and age-related diseases. Aging. Res. Rev. 8, 18-30. https://doi.org/10.1016/j.arr.2008.07.002
  12. Colbert, L. H., M. Visser, E. M. Simonsick, R. P. Tracy, A. B. Newman, S. B. Kritchevsky, M. Pahor, D. R. Taaffe, J. Brach, S. Rubin, and T. B. Harris. 2004. Physical activity, exercise, and inflammatory markers in older adults: findings from the health, aging and body composition study. J. Am. Geriatr. Soc. 52, 1098-1104. https://doi.org/10.1111/j.1532-5415.2004.52307.x
  13. de Somomayor, M. A., C. Perez-Guerrero, M. D. Herrrera, L. Jimenez, R. Marin, E. Marhuenda, and R. Andriantsitohaina. 2005. Improvement of age-related endothelial dysfunction by simvastatin: effect on NO and COX pathways. Br. J. Pharmacol. 146, 1130-1138.
  14. Ding, G., K. Reddy, A. A. Kapasi, N. Franki, N. Gibbons, B. S. Kasinath, and P. C. Singhal. 2002. Angiotensin II induces apoptosis in rat glomerular epithelial cells. Am. J. Physiol. Renal. Physiol. 283, 173-180.
  15. Dohi, Y., M. Kojima, K. Sato, and T. F. Luscher. 1995. Age-related changes in vascular smooth muscle and endothelium. Drugs Aging 7, 278-291. https://doi.org/10.2165/00002512-199507040-00003
  16. Feron, O., L. Belhassen, L. Kobzik, T. W. Smith, R. A. Kelly, and T. Michel. 1996. Endothelial nitric oxide synthase targeting to caveolae. Specific interactions with caveolin isoforms in cardiac myocytes and endothelial cells. J. Biol. Chem. 271, 22810-22814. https://doi.org/10.1074/jbc.271.37.22810
  17. Garcia-Cardena, G., P. Martasek, B. S. Siler-Masters, P. M. Skidd, J. C. Couet, S. Li, M. P. Lisanti, and W. C. Sessa. 1998. Dissecting the interaction between nitric oxide synthase (NOS) and caveolin: Functional significance of the NOS caveolin binding domain in vivo. J. Biol. Chem. 272, 25437-25440.
  18. Gerhard, M., M. A. Roddy, S. J. Creager, and M. A. Creager. 1996. Aging progressively impairs endothelium dependent vasorelaxation in forearm resistance vessles of humans. Hypertension 27, 849-853. https://doi.org/10.1161/01.HYP.27.4.849
  19. Graham, D. A. and J. W. Rush. 2004. Exercise training improves aortic endothelium-dependent vasorelaxation and determinants of nitric oxide bioavailability in spontaneously hypertension rats. J. Appl. Physiol. 96, 2088-2096. https://doi.org/10.1152/japplphysiol.01252.2003
  20. Green, D. J., G. O'Driscoll, B. A. Blanksby, and R. R. Taylor. 1996. Control skeletal muscle blood during dynamic exercise. Sports Med. 21, 119-146. https://doi.org/10.2165/00007256-199621020-00004
  21. Hambrecht, R., L. Hilbrich, S. Erbs, S. Gielen, E. Fiehn, N. Schuler, and G. Schuler. 2000. Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral L-arginine supplementation. J. Am. Coll. Cardiol. 35, 706-713. https://doi.org/10.1016/S0735-1097(99)00602-6
  22. Ishihata, A. and Y. Katano. 2006. Role of angiotensin II and endothelin-1 receptors in aging-related functional changes in rat cardiovascular system. Ann. N. Y. Acad. Sci. 1067, 173-181. https://doi.org/10.1196/annals.1354.021
  23. Jankord, R. and B. Jemiolo. 2004. Influence of physical activity on serum IL-6 and IL-10 levels in healthy older men. Med. Sci. Sports Exerc. 36, 960-964. https://doi.org/10.1249/01.MSS.0000128186.09416.18
  24. Linda, S. P., A. F. Barry, F. Robert, B. F. William, A. K. George, and A. R. Chester. 2004. Exercise and hypertension. Med. Sci. Sports Exercise 3603, 533-553.
  25. Lei, M., X. Hua, M. Xiao, J. Ding, Q. Han, and G. Hu. 2008. Impairments of astrocytes are involved in the D-galactose-induced brain aging. Biochem. Biophys. Res. Commun. 369, 1082-1087. https://doi.org/10.1016/j.bbrc.2008.02.151
  26. Long, J., X. Wang, H. Gao, Z. Liu, C. Liu, M. Miao, X. Cui, L. Packer, and J. Liu. 2007. D-Galactose toxicity in mice is associated with mitochindrial dysfunction: protection effects of mitochondrial nutrient R-alpha-lipoic acid. Biogerontology 8, 373-381. https://doi.org/10.1007/s10522-007-9081-y
  27. Makarov, S. 2000. NF-kappa B as a therapeutic target in chronic inflammation: recent advances. Mol. Med. Today 6, 441-448. https://doi.org/10.1016/S1357-4310(00)01814-1
  28. Moncada, S., R. M. Palmer, and E. A. Higgs. 1991. Nitric oxide: physiology and pharmacology. Pharmacol. Rev. 43, 109-142.
  29. Orozco-Gutiѐrrez, J. J., L. Castillo-Martinez, A. Orea- Tejeda, O. Vazquez-Diaz, A. Valdespino-Trejo, R. Narvaez-David, C. Keirns-Davis, O. Carrasco-Ortiz, A. Navarro-Navarro, and R. Sanchez-Santillan. 2010. Effect of L-arginine or L-citrulline oral supplementation on blood pressure and right ventricular function in heart failure patients with preserved ejection fraction. Cardiol. J. 17, 612-618
  30. Sessa, W. C., K. Pritchard, and N. I. Seyei. 1994. Chronic exercise in dogs increases coronary vascular nitric oxide production and endothelial cell nitric oxide synthase gene expression. Circ. Res. 74, 349-353. https://doi.org/10.1161/01.RES.74.2.349
  31. Seo, A. Y., T. Hofer, B. Sung, S. Judge, H. Y. Chung, and C. Leeuwenburgh. 2006. Hepatic oxidative stress during aging: effects of 8% long-term calorie restriction and lifelong exercise. Antioxid. Redox. Signal. 8, 529-538. https://doi.org/10.1089/ars.2006.8.529
  32. Song, X., M. Bao, D. Li, and Y. M. Li. 1999. Advanced glycation in D-galactose induced mouse aging model. Mech. Aging. Dev. 108, 239-251. https://doi.org/10.1016/S0047-6374(99)00022-6
  33. Wolf, G. 2002. Free radical production and angiotensin. Curr. Hypertens. Rep. 2, 167-173.
  34. Yamada, E. 1955. The fine structure of gall bladder epithelium of the mouse. J. Bio-phys. Biochem. Cytol. 1, 445-458. https://doi.org/10.1083/jcb.1.5.445

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