Abstract
We investigated the possible protective effect of atorvastatin against vascular dysfunction associated with insulin resistance (IR) in fructose-fed model rats. The effect of atorvastatin (10 mg/kg/day for 8 weeks) on vascular reactivity, glucose, cholesterol, insulin, and the IR index in a well-established model of dietary hypertriglyceridemia, the fructose-fed rat, was investigated. Fructose feeding (10% fructose in drinking water for 8 weeks) induced hypercholesterolemia and hyperinsulinemia without any change in blood glucose levels. Fructose feeding also elevated serum tumor necrosis factor-alpha (TNF-α), the insulin resistance index, leukocyte infiltration, and endothelial cell pyknosis. Fructose feeding induced hyper-responsiveness to both phenylephrine (PE), KCl, and hyporesponsiveness to acetylcholine (Ach) but not to sodium nitroprusside-induced relaxation. Atorvastatin, given concurrently with fructose, reduced hypercholesterolemia, hyperinsulinemia, TNF-α level, and the IR index. It also reduced leukocyte infiltration and endothelial cell pyknosis and decreased hyper-responsiveness to both PE and KCl but did not affect hyporesponsiveness to Ach relaxation. In conclusion, atorvastatin protected against impairment in aortic vascular reactivity associated with insulin resistance, particularly increased contractility, but not reduced endothelium-dependent relaxation, by a mechanism involving a reduction in cholesterol and IR in addition to anti-inflammatory effects.
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Allain, C. C., Poon, L. S., Chan, C. S., Richmond, W., and Fu, P. C., Enzymatic determination of total serum cholesterol. Clin. Chem., 20, 470–475 (1974).
Atsuta, J., Sterbinsky, S. A., Plitt, J., Schwiebert, L. M., Bochner, B. S., and Schleimer, R. P., Phenotyping and cytokine regulation of the BEAS-2B human bronchial epithelial cell, demonstration of inducible expression of the adhesion molecules VCAM-1 and ICAM-1. Am. J. Respir. Cell Mol. Biol., 17, 571–582 (1997).
Barham, D. and Trinder, P., An improved colour reagent for the determination of blood glucose by the oxidase system. Analyst, 97, 142–145 (1972).
Bartus, M., Lomnicka, M., Lorkowska, B., Franczyk, M., Kostogrys, R. B., Pisulewski, P. M., and Chlopicki, S., Hypertriglyceridemia but not hypercholesterolemia induces endothelial dysfunction in the rat. Pharmacol. Rep., 57, 127–137 (2005).
Basciano, H., Federico, L., and Adeli, K., Fructose, insulin resistance and metabolic dyslipidemia. Nutr. Metab., 2, 5 (2005).
Busija, D. W, Miller, A. W., Katakam, P., and Erdos, B., Adverse effects of reactive oxygen species on vascular reactivity in insulin resistance. Antioxid. Redox Signal., 8, 1131–1140 (2006).
Clarke, S., Protein isoprenylation and methylation at carboxyl-terminal cysteine residues. Annu. Rev. Biochem., 61, 355–386 (2006).
Corda, S., Laplace, C., Vicaut, E., and Duranteau, J., Rapid reactive oxygen species production by mitochondria in endothelial cells exposed to tumor necrosis factor-á is mediated by ceramide. Am. J. Respir. Cell Mol. Biol., 24, 762–768 (2001).
Dai, S., Todd, M. E., Lee, S., and McNeill, J. H., Fructose loading induces cardiovascular and metabolic changes in nondiabetic and diabetic rats. Can. J. Physiol. Pharmacol., 72, 771–781 (1994).
Dai, S. and McNeill, J. H., Fructose-induced hypertension in rats is concentration- and duration-dependent. J. Pharmacol. Toxicol. Methods, 33, 101–107 (1995).
Dillmann, W. H., Fructose feeding increases Ca++-activated myosin ATPase activity and changes myosin isoenzyme distribution in the diabetic rat heart. Endocrinology, 114, 1678–1685 (1984).
Erdos, B., Miller, A. W., and Busija, D. W., Impaired endothelium-mediated relaxation in isolated cerebral arteries from insulin-resistant rats. Am. J. Physiol. Heart Circ. Physiol., 282, H2060–H2065 (2002).
Fasolato, C., Innocenti, B., and Pozzan, T., Receptoractivated Ca2+ influx: how many mechanisms for how many channels? Trends Pharmacol. Sci., 15, 77–83 (1994).
Ferro, T. J., Hocking, D. C., and Johnson, A., Tumor necrosis factor-alpha alters pulmonary vasoreactivity via neutrophil-derived oxidants. Am. J. Physiol., 265, L462–L471 (1993).
Forcillo, J., Maltais, S., Aubin, M. C., Shi, Y. F., Carrier, M., Tardif, J. C., and Perrault, L. P., Atorvastatin worsens left ventricular diastolic dysfunction and endothelial dysfunction of epicardial coronary arteries in normocholesterolemic porcine with left ventricular hypertrophy. J. Cardiovasc. Pharmacol., 58, 295–306 (2011).
Goldstein, J. L. and Brown, M. S., Regulation of the mevalonate pathway. Nature, 343, 425–430 (1990).
Goodwill, A. G., Frisbee, S. J., Stapleton, P. A., James, M. E., and Frisbee, J. C., Impact of chronic anticholesterol therapy on development of microvascular rarefaction in the metabolic syndrome. Microcirculation, 16, 667–684 (2009).
Hancock, J. F., Magee, A. I., Childs, J. E., and Marshall, C. J., All ras proteins are polyisoprenylated but only some are palmitoylated. Cell, 57, 1167–1177 (1989).
Heitzer, T., Schlinzig, T., Krohn, K., Meinertz, T., and Münzel, T., Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation, 104, 2673–2678 (2001).
Hwang, I. S., Ho, H., Hoffman, B. B., and Reaven, G. M., Fructose-induced insulin resistance and hypertension in rats. Hypertension, 10, 512–516 (1987).
Iyer, S. N. and Katovich, M. J., Vascular reactivity to phenylephrine and angiotensin II in hypertensive rats associated with insulin resistance. Clin. Exp. Hypertens., 18, 227–242 (1996).
Laufs, U., La Fata, V., Plutzky, J., and Liao, J. K., Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation, 97, 1129–1135 (1998).
Mach, F., Montecucco, F., and Steffens, S., Cannabinoid receptors in acute and chronic complications of atherosclerosis. Br. J. Pharmacol., 153, 290–298 (2008).
Marchesi, S., Lupattelli, G., Siepi, D., Schillaci, G., Vaudo, G., Roscini, A. R., Sinzinger, H., and Mannarino, E., Short-term atorvastatin treatment improves endothelial function in hypercholesterolemic women. J. Cardiovasc. Pharmacol., 36, 617–621 (2000).
Matthews, D. R., Hosker, J. P., Rudenski, A. S., Naylor, B. A., Treacher, D. F., and Turner, R. C., Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 28, 412–419 (1985).
Maugeri, N., Rovere-Querini, P., Baldini, M., Sabbadini, M. G., and Manfredi, A. A., Translational mini-review series on immunology of vascular disease: mechanisms of vascular inflammation and remodelling in systemic vasculitis. Clin. Exp. Immunol., 156, 395–404 (2009).
McNeill, K. L., Fontana, L., Russell-Jones, D. L., Rajman, I., Ritter, J. M., and Chowienczyk, P. J., Inhibitory effects of low-density lipoproteins from men with type II diabetes on endothelium-dependent relaxation. J. Am. Coll. Cardiol., 35, 1622–1627 (2000).
Miller, A. and Adeli, K, Dietary fructose and the metabolic syndrome. Curr. Opin. Gastroenterol., 24, 204–209 (2008).
Navarro-Cid, J., Maeso, R., Perez-Vizcaino, F., Cachofeiro, V., Ruilope, L. M., Tamargo, J., and Lahera, V., Effects of losartan on blood pressure, metabolic alterations, and vascular reactivity in the fructose-induced hypertensive rat. Hypertension, 26, 1074–1078 (1995).
Perticone, F., Ceravolo, R., Pujia, A., Ventura, G., Iacopino, S., Scozzafava, A., Ferraro, A., Chello, M., Mastroroberto, P., Verdecchia, P., and Schillaci, G., Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation, 104, 191–196 (2001).
Piepot, H. A., Groeneveld, A. B., Van Lambalgen, A. A., and Sipkema, P., Tumor necrosis factor-alpha impairs endothelium-dependent relaxation of rat renal arteries, independent of tyrosine kinase. Shock, 17, 394–398 (2002).
Pretnar-Oblak, J., Sebestjen, M., and Sabovic, M., Statin treatment improves cerebral more than systemic endothelial dysfunction in patients with arterial hypertension. Am. J. Hypertens., 21, 674–678 (2008).
Ruegg, U. T., Wallnofer, A., Weir, S., and Cauvin, C., Receptor-operated calcium-permeable channels in vascular smooth muscle. J. Cardiovasc. Pharmacol., 14, S49–58 (1989).
Shinozaki, K., Ayajiki, K., Nishio, Y., Sugaya, T., Kashiwagi, A., and Okamura, T., Evidence for a causal role of the renin-angiotensin system in vascular dysfunction associated with insulin resistance. Hypertension, 43, 255–262 (2004).
Sodha, N. R., Boodhwani, M., Ramlawi, B., Clements, R. T., Mieno, S., Feng, J., Xu, S. H., Bianchi, C., and Sellke, F. W., Atorvastatin increases myocardial indices of oxidative stress in a porcine model of hypercholesterolemia and chronic ischemia. J. Card. Surg., 23, 312–320 (2008).
Taghibiglou, C., Carpentier, A., Van Iderstine, S. C., Chen, B., Rudy, D., Aiton, A., Lewis, G. F., and Adeli, K., Mechanisms of hepatic very low-density lipoprotein overproduction in insulin resistance. Evidence for enhanced lipoprotein assembly, reduced intracellular ApoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model. J. Biol. Chem., 275, 8416–8425 (2000).
Takagawa, Y., Berger, M. E., Hori, M. T., Tuck, M. L., and Golub, M. S., Long-term fructose feeding impairs vascular relaxation in rat mesenteric arteries. Am. J. Hypertens., 14, 811–817 (2001).
Tesfamariam, B., Frohlich, B. H., and Gregg, R. E., Differential effects of pravastatin, simvastatin, and atorvastatin on Ca2+ release and vascular reactivity. J. Cardiovasc. Pharmacol., 34, 95–101 (1999).
Torrens, C., Kelsall, C. J., Hopkins, L. A., Anthony, F. W., Curzen, N. P., and Hanson, M. A., Atorvastatin restores endothelial function in offspring of protein-restricted rats in a cholesterol-independent manner. Hypertension, 53, 661–667 (2009).
Tran, L. T, Yuen, V. G., and McNeill, J. H., The fructose-fed rat, a review on the mechanisms of fructose-induced insulin resistance and hypertension. Mol. Cell. Biochem., 332, 145–159 (2009).
Vakkilainen, J., Mäkimattila, S., Seppälä-Lindroos, A., Vehkavaara, S., Lahdenperä, S., Groop, P. H., Taskinen, M. R., and Yki-Järvinen, H., Endothelial dysfunction in men with small LDL particles. Circulation, 102, 716–721 (2000).
Van Etten, R. W., De Koning, E. J., Honing, M. L., Stroes, E. S., Gaillard, C. A., and Rabelink, T. J., Intensive lipid lowering by statin therapy does not improve vasoreactivity in patients with type 2 diabetes. Arterioscler. Thromb. Vasc. Biol., 22, 799–804 (2002).
Van Venrooij, F. V., van de Ree, M. A., Bots, M. L., Stolk, R. P., Huisman, M. V., and Banga, J. D., Aggressive lipid lowering does not improve endothelial function in type 2 diabetes, the Diabetes Atorvastatin Lipid Intervention (DALI) Study, a randomized, Double blind, placebo-controlled trial. Diabetes Care, 25, 1211–1216 (2002).
Verma, S., Bhanot, S., Yao, L., and McNeill, J. H., Defective endothelium-dependent relaxation in fructose-hypertensive rats. Am. J. Hypertens., 9, 370–376 (1996).
Viswanad, B., Srinivasan, K., Kaul, C. L., and Ramarao, P., Effect of tempol on altered angiotensin II and acetylcholine-mediated vascular responses in thoracic aorta isolated from rats with insulin resistance. Pharmacaol. Res., 53, 209–215 (2006).
Weyand, C. M., Ma-Krupa, W., and Goronzy, J. J., Immunopathways in giant cell arteritis and polymyalgia rheumatica. Autoimmun. Rev., 3, 46–53 (2004).
Yki-Järvinen, H., Prediction and prevention of non-insulindependent diabetes mellitus, In Williams, G. and Pickup, J. (Eds.). Textbook of Diabetes. Blackwell, Oxford, pp. 83.1–83.13, (2001).
Yoshino, G., Iwai, M., Kazumi, T., Matsushita, M., Morita, M., Matsuba, K., Iwatani, I., and Baba, S., Effect of dietary fructose on triglyceride turnover in streptozotocin-diabetic rats. Atherosclerosis, 79, 41–46 (1989).
Zeng, Z. H., Zhang, Z. H., Luo, B. H., He, W. K., Liang, L. Y., He, C. C., and Su, C. J., The functional changes of the perivascular adipose tissue in spontaneously hypertensive rats and the effects of atorvastatin therapy. Clin. Exp. Hypertens., 31, 355–363 (2009).
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Mahmoud, M.F., El-Nagar, M. & El-Bassossy, H.M. Anti-inflammatory effect of atorvastatin on vascular reactivity and insulin resistance in fructose fed rats. Arch. Pharm. Res. 35, 155–162 (2012). https://doi.org/10.1007/s12272-012-0117-8
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DOI: https://doi.org/10.1007/s12272-012-0117-8