Letter to the editor: Is homocysteine the culprit molecule in vascular diseases or just a bystander?

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299:873-, 2010. doi:10.1152/ajpcell.00164.2010

Am J Physiol Cell Physiol

Shao-Chun Lu, Yi-Jie Chen and Po-Yuan Chang

molecule in vascular diseases or just a bystander?

Letter to the editor: Is homocysteine the culprit

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Letter to the editor: Is homocysteine the culprit molecule in vascular diseases

or just a bystander?

Shao-Chun Lu,1Yi-Jie Chen,1and Po-Yuan Chang2

1Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine and2Department

of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

TO THE EDITOR: Jiang et al. (3) reported an important finding that

vascular smooth cell migration was promoted by the resistin gene expression induced by ultrahigh concentrations of homo-cysteine (500␮M). The homocysteine concentrations used by Jiang et al. were markedly higher than the physiological concentrations (⬍100 ␮M); therefore, the biological signifi-cance of the results of their study should be interpreted with caution. Since supraphysiological concentrations of homocys-teine are required to induce resistin expression, the role of homocysteine in vascular cell migration is debatable. To assess the effects of homocysteine at physiological levels, Wang et al. (5) developed a method in which erythro-9 (2-hydroxy-3-nonyl)-adenine hydrochloride (EHNA) and adenosine were added to homocysteine to convert homocysteine into its more toxic form S-adenosylhomocysteine (SAH). This protocol has been used in many studies to study the effects of homocysteine on gene expression.

The effect of homocysteine on the downregulation of fibro-blast growth factor 2 (FGF2) in human coronary artery endo-thelial cells (HCAECs) is mediated through SAH and not by homocysteine itself (2). We have previously reported that a supraphysiological concentration (500 ␮M) of homocyteine did not affect the cell integrity of HCAECs. However, when EHNA was added to the cell culture to facilitate the formation of intracellular SAH, homocysteine induced cytotoxic changes at concentrations as low as 25 ␮M, which is a clinically relevant concentration. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) revealed that cells exposed to homocysteine and adenosine/EHNA showed at least a two- to fourfold increase in intracellular SAH concen-tration. In conclusion, we hypothesize that in the absence of SAH, the vascular effects of homocysteine will be negligible even at supraphysiological concentrations of homocysteine.

The indispensable role of SAH, and not homocysteine, in inducing vascular endothelial damage explains the lack of health benefits in several nutritional intervention trials, despite the increase in vitamin supplements to successfully lower plasma homocysteine levels (1). Since growing evidence sug-gests that SAH is a better indicator of cardiovascular disease than homocysteine (4), Jiang et al. may want to delineate the relative importance of SAH in resistin regulation in compari-son with that of homocysteine in their future studies.

GRANTS

This work was supported by research Grants NSC 91-2320-B-002-185, 93-2314-B-002-125, 94-2320-B-002-121, 95-2320-B-002-116, and 98-2628-B-002-088 from the National Science Council, Taiwan, and Grants NTUH92A14, 93A02, 95S342, and 96S643 from National Taiwan University Hospital, Taiwan.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s). REFERENCES

1. Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Daniel-son E, Buring JE, ManDaniel-son JE. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA 299: 2027–2036, 2008. 2. Chang PY, Lu SC, Lee CM, Chen YJ, Dugan TA, Huang WH, Chang

SF, Liao WS, Chen CH, Lee YT. Homocysteine inhibits arterial endothe-lial cell growth through transcriptional downregulation of FGF2 involving G protein and DNA methylation. Circ Res 102: 933–941, 2008. 3. Jiang C, Zhang H, Zhang W, Kong W, Zhu Y, Zhang H, Xu Q, Li Y,

Wang X. Homocysteine promotes vascular smooth muscle cell migration by induction of the adipokine resistin. Am J Physiol Cell Physiol 297: C1466 –C1476, 2009.

4. Kerins DM, Koury MJ, Capdevila A, Rana S, Wagner C. Plasma S-adenosylhomocysteine is a more sensitive indicator of cardiovascular disease than plasma homocysteine. Am J Clin Nutr 74: 723–729, 2001. 5. Wang H, Yoshizumi M, Lai K, Tsai JC, Perrella MA, Haber E, Lee

ME. Inhibition of growth and p21ras methylation in vascular endothelial cells by homocysteine but not cysteine. J Biol Chem 272: 25380 –25385, 1997.

Address for reprint requests and other correspondence: P.-Y. Chang, Dept. of Internal Medicine, National Taiwan Univ. College of Medicine, Taipei, Taiwan (e-mail: pychang@ntu.edu.tw).

Am J Physiol Cell Physiol 299: C873, 2010;

doi:10.1152/ajpcell.00164.2010. Letter To The Editor

0363-6143/10 Copyright©2010 the American Physiological Society

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