Advertisement

Molecular Medicine

, Volume 14, Issue 7–8, pp 395–402 | Cite as

Felodipine Reduces Cardiac Expression of IL-18 and Perivascular Fibrosis in Fructose-Fed Rats

  • Shan-Shan Xing
  • Hong-Wei Tan
  • Xiu-Ping Bi
  • Ming Zhong
  • Yun Zhang
  • Wei Zhang
Research Article

Abstract

Metabolic syndrome is associated with accelerated macrovascular and microvascular coronary disease, cardiomyopathy, and elevated inflammatory status. To determine whether metabolic syndrome-associated elevation of the inflammatory cytokine interleukin-18 (IL-18) in serum and cardiac tissue, and its potential sequelae could be attenuated pharmacologically, we studied fructose-fed rats. The fructose-fed rats exhibited increases in systolic blood pressure (SBP), body weight, heart weight, left ventricular weight, and blood insulin. Serum IL-18 levels in these rats were also elevated significantly. These changes were significantly different compared to those in control rats. Perivascular fibrosis around coronary arterioles was evident in the fructose-fed rats, accompanied by a paralleled increase in IL-18 by immunohistochemical analysis and real time polymerase chain reaction. Felodipine attenuated the increased levels in serum IL-18 and cardiac IL-18 mRNA as well as coronary perivascular fibrosis. Thus, augmented IL-18 in serum and cardiac tissue in metabolic syndrome may contribute to the coronary perivascular fibrosis; felodipine administration can attenuate the inflammatory and fibrosis process.

Notes

Acknowledgments

This study was supported by the National Natural Science Foundation of P. R. China (No. 30670874 to W Zhang) and by the research funding of Astra-Zeneca Pharmaceutical Co. Ltd., China (QD02 to W Zhang).

References

  1. 1.
    Bonora E et al. (2003) Carotid atherosclerosis and coronary heart disease in the metabolic syndrome: prospective data from the Bruneck study. Diabetes Care. 26:1251–7.CrossRefGoogle Scholar
  2. 2.
    Reilly MP et al. (2004) Measures of insulin resistance add incremental value to the clinical diagnosis of metabolic syndrome in association with coronary atherosclerosis. Circulation. 110:803–9.CrossRefGoogle Scholar
  3. 3.
    Reaven GM. (1988) Banting lecture 1988: role of insulin resistance in human disease. Diabetes. 37:1595–607.CrossRefGoogle Scholar
  4. 4.
    Meigs JB. (2000) Invited commentary: insulin resistance syndrome? Syndrome X? Multiple metabolic syndrome? A syndrome at all? Factor analysis reveals patterns in the fabric of correlated metabolic risk factors. Am. J. Epidemiol. 152:908–12.CrossRefGoogle Scholar
  5. 5.
    Sakkinen PA, Wahl P, Cushman M, Lewis MR, Tracy RP. (2000) Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. Am. J. Epidemiol 152:897–907.CrossRefGoogle Scholar
  6. 6.
    Zaman AK et al. (2004) Salutary effects of attenuation of angiotensin II on coronary perivascular fibrosis associated with insulin resistance and obesity. J. Mol. Cell. Cardiol. 37:525–35.CrossRefGoogle Scholar
  7. 7.
    Reaven GM. (1988) Role of insulin resistance in human disease. Diabetes. 37:1595–606.CrossRefGoogle Scholar
  8. 8.
    Haffner S, Taegtmeyer H. (2003) Epidemic obesity and the metabolic syndrome. Circulation. 108:1541–5.CrossRefGoogle Scholar
  9. 9.
    Murakami H, Urabe K, Nishimura M. (1998) Inappropriate microvascular constriction produced transient ST-segment elevation in patients with syndrome X. J. Am. Coll. Cardiol. 32:1287–94.CrossRefGoogle Scholar
  10. 10.
    Pickup JC, Mattock MB, Chusney GD, Burt D. (1997) NIDDM as a disease of the innate immune system: association of acute-phase reactants and IL-6 with metabolic syndrome X. Diabetologia. 40:1286–92.CrossRefGoogle Scholar
  11. 11.
    Pickup JC. (2004) Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care. 27:813–23.CrossRefGoogle Scholar
  12. 12.
    Biondi-Zoccai GG, Abbate A, Liuzzo G, Biasucci LM. (2003) Atherothrombosis, inflammation, and diabetes. J. Am. Coll. Cardiol. 41:1071–7.CrossRefGoogle Scholar
  13. 13.
    Okamura H, Tsutsui H, Kashiwamura S, Yoshimoto T, Nakanishi K. (1998) Interleukin-18: a novel cytokine that augments both acquired and innate immunity. Adv. Immunol. 70:281–312.CrossRefGoogle Scholar
  14. 14.
    Gracie JA, Robertson SE, McInnes IB. (2003) Interleukin-18. J. Leukoc. Biol. 73:213–24.CrossRefGoogle Scholar
  15. 15.
    Mallat Z et al. (2001) Expression of IL-18 in human atherosclerotic plaques and relation to plaque instability. Circulation. 104:1598–603.CrossRefGoogle Scholar
  16. 16.
    Blankenberg S et al. (2002) Athero Gene Investigators. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation. 106:24–30.CrossRefGoogle Scholar
  17. 17.
    Blankenberg S et al. (2003) PRIME Study Group. IL-18 and the risk of coronary heart disease in European men: the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation. 108:2453–9.CrossRefGoogle Scholar
  18. 18.
    Esposito K. et al. (2002) Weight loss reduces IL-18 levels in obese women. J. Clin. Endocrinol. Metab. 87:3864–6.CrossRefGoogle Scholar
  19. 19.
    Escobar-Morreale HF, Botella-Carretero JI, Villuendas G, Sancho J, San Millan JL. (2004) Serum IL-18 concentrations are increased in the polycystic ovary syndrome: relationship to insulin resistance and to obesity. J. Clin. Endocrinol. Metab. 89:806–11.CrossRefGoogle Scholar
  20. 20.
    Esposito K et al. (2002) Inflammatory cytokine concentrations are acutely increased by hyper-glycemia in humans: role of oxidative stress. Circulation. 106:2067–72.CrossRefGoogle Scholar
  21. 21.
    Esposito K et al. (2003) Cytokine milieu tends toward inflammation in type 2 diabetes. Diabetes Care. 26:1647.CrossRefGoogle Scholar
  22. 22.
    Aso Y, Okumura K, Takebayashi K, Wakabayashi S, Inukai T. (2003) Relationships of plasma IL-18 concentrations to hyperhomocysteinemia and carotid intimal-media wall thickness in patients with type 2 diabetes. Diabetes Care. 26:2622–7.CrossRefGoogle Scholar
  23. 23.
    Stetler-Stevenson WG. (1999) Matrix metallopro-teinases in angiogenesis: a moving target for therapeutic intervention. J. Clin. Invest. 103:1237–41.CrossRefGoogle Scholar
  24. 24.
    El Messal M et al. (2006) Elevated serum levels of proinflammatory cytokines and biomarkers of matrix remodeling in never-treated patients with familial hypercholesterolemia. Clin. Chim. Acta. 366:185–9.CrossRefGoogle Scholar
  25. 25.
    Miatello R et al. (2005) Chronic administration of resveratrol prevents biochemical cardiovascular changes in fructose-fed rats. Am. J. Hypertens. 18:864–70.CrossRefGoogle Scholar
  26. 26.
    Huang BW, Chiang MT, Yao HT, Chiang W. (2004) The effect of high-fat and high-fructose diets on glucose tolerance and plasma lipid and leptin levels in rats. Diabetes Obes. Metab. 6:120–6.CrossRefGoogle Scholar
  27. 27.
    Hishikawa K, Lüscher TF. (1998) Felodipine inhibits free-radical production by cytokines and glucose in human smooth muscle cells. Hypertension. 32:1011–5.CrossRefGoogle Scholar
  28. 28.
    Rödler S, Roth M, Nauck M, Tamm M, Block LH. (1995) Ca(2+)-channel blockers modulate the expression of interleukin-6 and interleukin-8 genes in human vascular smooth muscle cells. J. Mol. Cell. Cardiol. 27:2295–302.CrossRefGoogle Scholar
  29. 29.
    Bunag RD. (1973) Validation in awake rats of a tail-cuff method for measuring systolic pressure. J. Appl. Physiol. 34:279–82.CrossRefGoogle Scholar
  30. 30.
    Bunag RD. (1994) Blood pressure measurement in rats. In: Garten D, De Jong W. Experimental and genetic models of hypertension. Handbook of hypertension, vol 16. Amsterdam: Elsevier, pp:1–17.Google Scholar
  31. 31.
    Matthews DR et al. (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 28:412–9.CrossRefGoogle Scholar
  32. 32.
    Masson P. (1992) Trichrome stainings and their preliminary technique. J. Tech. Methods. 2:75–90.Google Scholar
  33. 33.
    Livak KJ, Schmittgen TD. (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2 (-Delta Delta C(T)) Method. Methods. 25:402–8.CrossRefGoogle Scholar
  34. 34.
    Basciano H, Federico L, Adeli K. (2005) Fructose, insulin resistance, and metabolic dyslipidemia. Nutr. Metab. 2:5.CrossRefGoogle Scholar
  35. 35.
    Frohlich M et al. (2000) Association between C-reactive protein and features of the metabolic syndrome: a population-based study. Diabetes Care. 23:1835–9.CrossRefGoogle Scholar
  36. 36.
    Festa A et al. (2000) Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation. 102:42–7.CrossRefGoogle Scholar
  37. 37.
    Sakkinen PA, Wahl P, Cushman M, Lewis MR, Tracy RP. (2000) Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. Am. J. Epidemiol. 152:897–907.CrossRefGoogle Scholar
  38. 38.
    Hak AE et al. (2001) Markers of inflammation and cellular adhesion molecules in relation to insulin resistance in nondiabetic elderly: the Rotterdam study. J. Clin. Endocrinol. Metabol. 86:4398–405.CrossRefGoogle Scholar
  39. 39.
    Hung J, McQuillan BM, Chapman CM, Thompson PL, Beilby JP. (2005) Elevated interleukin-18 levels are associated with the metabolic syndrome independent of obesity and insulin resistance. Arterioscler. Thromb. Vasc. Biol. 25:1268–73.CrossRefGoogle Scholar
  40. 40.
    Zirlik A et al. (2007) Interleukin-18, the metabolic syndrome, and subclinical atherosclerosis: results from the Dallas Heart Study. Arterioscler. Thromb. Vasc. Biol. 27:2043–9.CrossRefGoogle Scholar
  41. 41.
    Greenberg AS, McDaniel ML. (2002) Identifying the links between obesity, insulin resistance and beta-cell function: potential role of adipocyte adipocyte-derived cytokines in the pathogenesis of type 2 diabetes. Eur. J. Clin. Invest. 32:24–34.CrossRefGoogle Scholar
  42. 42.
    McLaughlin T et al. (2002) Differentiation between obesity and insulin resistance in the association with C-reactive protein. Circulation. 106:2908–12.CrossRefGoogle Scholar
  43. 43.
    Reddy VS et al. (2008) Interleukin-18 stimulates fibronectin expression in primary human cardiac fibroblasts via PI3K-Akt-dependent NF-kappaB activation. J. Cell. Physiol. 215:697–707.CrossRefGoogle Scholar
  44. 44.
    Gerdes N et al. (2002) Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis. J. Exp. Med. 195:245–57.CrossRefGoogle Scholar
  45. 45.
    Abaci A et al. (1999) Effect of diabetes mellitus on formation of coronary collateral vessels. Circulation. 99:2239–42.CrossRefGoogle Scholar
  46. 46.
    Schaper W, Buschmann I. (1999) Collateral circulation and diabetes. Circulation. 99:2224–6.CrossRefGoogle Scholar
  47. 47.
    Zaman AK et al. (2001) Angiotensin-converting enzyme inhibition attenuates hypofibrinolysis and reduces cardiac perivascular fibrosis in genetically obese diabetic mice. Circulation. 103: 3123–8.CrossRefGoogle Scholar
  48. 48.
    Matsumori A, Nunokawa Y, Sasayama S. (2000) Nifedipine inhibits activation of transcription factor NF-kappaB. Life Sci. 67:2655–61.CrossRefGoogle Scholar
  49. 49.
    Iwasaki Y et al. (2004) Nilvadipine inhibits nuclear factor-kappaB-dependent transcription in hepatic cells. Clin. Chim. Acta. 350:151–7.CrossRefGoogle Scholar
  50. 50.
    Matsubara M, Hasegawa K. (2004) Effects of benidipine, a dihydropyridine-Ca2+ channel blocker, on expression of cytokine-induced adhesion molecules and chemoattractants in human aortic endothelial cells. Eur. J. Pharmacol. 498:303–14.CrossRefGoogle Scholar
  51. 51.
    Ding Y, Vaziri ND. (1998) Calcium channel blockade enhances nitric oxide synthase expression by cultured endothelial cells. Hypertension. 32:718–23.CrossRefGoogle Scholar
  52. 52.
    Jesmin S et al. (2006) Subdepressor dose of benidipine ameliorates diabetic cardiac remodeling accompanied by normalization of upregulated endothelin system in rats. Am. J. Physiol. Heart Circ. Physiol. 290:2146–54.CrossRefGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2008

Authors and Affiliations

  • Shan-Shan Xing
    • 1
  • Hong-Wei Tan
    • 1
  • Xiu-Ping Bi
    • 1
  • Ming Zhong
    • 1
  • Yun Zhang
    • 1
  • Wei Zhang
    • 1
  1. 1.Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health; Department of Cardiology, QiLu HospitalShandong UniversityJinanChina

Personalised recommendations