HDL-Mediated Protection of Coronary Vasodilator Response to Adenosine in the Hypercholesterolemic Swine

DOI: 10.4236/ojmip.2014.44006   PDF   HTML   XML   3,309 Downloads   3,755 Views  


It is known that high-cholesterol diet impairs coronary vasodilatation in animal models of athe-rosclerosis irrespective of overt pathology. We evaluated the specific role of LDL and HDL on adenosine-elicited coronary vasodilatation after short time (10 weeks) high-cholesterol diet in pigs. Nineteen pigs on standard (C), atherogenic (HF) and alternate standard or atherogenic diet every other week (IHF) underwent left coronary angiography and flow (CFR) measurement during intracoronary adenosine injection. Total cholesterol, HDL, LDL, Apo lipoprotein A-1, IL-6, TNF-α and ICAM-1 were measured and histology of coronary samples was performed. IHF and HF show comparable intimal thickening of lesions, similar cholesterol (598.4 ± 198.2 and 633.2 ± 83.5 mg/dL) and LDL (502.6 ± 193.7 and 576.1 ± 83.2), while HDL is double in IHF group (88.3 ± 6.4 vs 46.4 ± 18.7 p < 0.0001). Vasodilation is reduced in HF (CFR = 1.6 ± 0.2, p < 0.001) as compared to C (2.6 ± 0.4), whilst it is preserved in IHF (2.7 ± 0.4). CFR and HDL values of all hypercholesterolemia cases are positively correlated (r = 0.88, p < 0.001). No relation with cytokines/cell adhesion markers is present. These findings suggest for the first time that elevation of plasma HDL level counteracts LDL related vasodilation impairment during coronary atherogenesis in swine.

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Vozzi, F. , Pelosi, G. , Puntoni, M. , Viglione, F. , Rocchiccioli, S. , Kusmic, C. , Bernini, F. , Marraccini, P. , Trivella, M. and Parodi, O. (2014) HDL-Mediated Protection of Coronary Vasodilator Response to Adenosine in the Hypercholesterolemic Swine. Open Journal of Molecular and Integrative Physiology, 4, 49-61. doi: 10.4236/ojmip.2014.44006.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Abebe, W. and Mustafa, S.J. (1997) Effect of Low Density Lipoprotein on Adenosine Receptor-Mediated Coronary Vasorelaxation in Vitro. Journal of Pharmacology and Experimental Therapeutics, 282, 851-857.
[2] Rodriguez-Porcel, M., Lerman, A., Ritman, E.L., et al. (2000) Altered Myocardial Microvascular 3D Architecture in Experimental Hypercholesterolemia. Circulation, 102, 2028-2030.
[3] Rodriguez-Porcel, M., Lerman, A., Best, P.J., et al. (2001) Hypercholesterolemia Impairs Myocardial Perfusion and Permeability: Role of Oxidative Stress and Endogenous Scavenging Activity. Journal of the American College of Cardiology, 37, 608-615.
[4] Theilmeier, G., Verhamme, P., Dymarkowski, S., et al. (2002) Hypercholesterolemia in Minipigs Impairs Left Ventricular Response to Stress: Association with Decreased Coronary Flow Reserve and Reduced Capillary Density. Circulation, 106, 1140-1146.
[5] Mathew, V., Cannan, C.R., Miller, V.M., et al. (1997) Enhanced Endothelin-Mediated Coronary Vasoconstriction and Attenuated Basal Nitric Oxide Activity in Experimental Hypercholesterolemia. Circulation, 96, 1930-1936.
[6] Chen, C.H. and Henry, P.D. (1997) Atherosclerosis as a Microvascular Disease: Impaired Angiogenesis Mediated by Suppressed Basic Fibroblast Growth Factor Expression. Proceedings of the Association of American Physicians, 109, 351-361.
[7] Mannheim, D., Versari, D., Daghini, E., et al. (2007) Impaired Myocardial Perfusion Reserve in Experimental Hypercholesterolemia Is Independent of Myocardial Neovascularization. American Journal of Physiology—Heart and Circulatory Physiology, 292, H2449-H2458.
[8] Bender, S.B., Tune, J.D., Borbouse, L., et al. (2009) Altered Mechanism of Adenosine-Induced Coronary Arteriolar Dilation in Early-Stage Metabolic Syndrome. Experimental Biology and Medicine (Maywood), 234, 683-692.
[9] Heaps, C.L., Jeffery, E.C., Laine, G.A., et al. (2008) Effects of Exercise Training and Hypercholesterolemia on Adenosine Activation of Voltage-Dependent K+ Channels in Coronary Arterioles. Journal of Applied Physiology, 105, 1761-1771.
[10] Borbouse, L., Dick, G.M., Payne, G.A., et al. (2010) Metabolic Syndrome Reduces the Contribution of K+ Channels to Ischemic Coronary Vasodilation. American Journal of Physiology—Heart and Circulatory Physiology, 298, H1182-H1189.
[11] Wang, W., Hein, T.W., Zhang, C., Zawieja, D.C., Liao, J.C. and Kuo, L. (2010) Oxidized Low-Density Lipoprotein Inhibits Nitric Oxide-Mediated Coronary Arteriolar Dilation by Up-Regulating Endothelial Arginase I. Microcirculation, 18, 36-45.
[12] Zeiher, A.M., Drexler, H., Wollschläger, H. and Just, H. (1991) Endothelial Dysfunction of the Coronary Microvasculature Is Associated with Coronary Blood Flow Regulation in Patients with Early Atherosclerosis. Circulation, 84, 1984-1992.
[13] Seiler, C., Hess, O.M., Buechi, M., Suter, T.M. and Krayenbuehl, H.P. (1993) Influence of Serum Cholesterol and Other Coronary Risk Factors on Vasomotion of Angiographically Normal Coronary Arteries. Circulation, 88, 2139-2148.
[14] Drexler, H., Zeiher, A.M., Meinzer, K. and Just, H. (1991) Correction of Endothelial Dysfunction in Coronary Microcirculation of Hypercholesterolaemic Patients by L-Arginine. Lancet, 338, 1546-1550.
[15] Creager, M.A., Gallagher, S.J., Girerd, X.J., Coleman, S.M., Dzau, V.J. and Cooke, J.P. (1992) L-Arginine Improves Endothelium-Dependent Vasodilation in Hypercholesterolemic Humans. Journal of Clinical Investigation, 90, 1248- 1253.
[16] Leung, W.H., Lau, C.P. and Wong, C.K. (1993) Beneficial Effect of Cholesterol-Lowering Therapy on Coronary Endothelium-Dependent Relaxation in Hypercholesterolaemic Patients. The Lancet, 341, 1496-1500.
[17] Egashira, K., Hirooka, Y., Kai, H., Sugimachi, M., Suzuki, S., Inou, T. and Takeshita, A. (1994) Reduction in Serum Cholesterol with Pravastatin Improves Endothelium-Dependent Coronary Vasomotion in Patients with Hypercholesterolemia. Circulation, 89, 2519-2524.
[18] Treasure, C.B., Klein, J.L., Weintraub, W.S., Talley, J.D., Stillabower, M.E., Kosinski, A.S., et al. (1995) Beneficial Effects of Cholesterol-Lowering Therapy on the Coronary Endothelium in Patients with Coronary Artery Disease. New England Journal of Medicine, 332, 481-487.
[19] Anderson, T.J., Meredith, I.T., Yeung, A.C., Frei, B., Selwyn, A.P. and Ganz, P. (1995) The Effect of Cholesterol-Lowering and Antioxidant Therapy on Endothelium-Dependent Coronary Vasomotion. New England Journal of Medicine, 332, 488-493.
[20] Matsuda, Y., Hirata, K., Inoue, N., Suematsu, M., Kawashima, S., Akita, H. and Yokoyama, M. (1993) High Density Lipoprotein Reverses Inhibitory Effect of Oxidized Low Density Lipoprotein on Endothelium-Dependent Arterial Relaxation. Circulation Research, 72, 1103-1109.
[21] Bisoendial, R.J., Hovingh, G.K., Levels, J.H.M., Lerch, P.G., Andresen, I., Hayden, M.R., et al. (2003) Restoration of Endothelial Function by Increasing High-Density Lipoprotein in Subjects with Isolated Low High-Density Lipoprotein. Circulation, 107, 2944-2948.
[22] Kaufmann, P.A., Gnecchi-Ruscone, T., Schäfers, K.P., Lüscher, T.F. and Camici, P.G. (2000) Low Density Lipoprotein Cholesterol and Coronary Microvascular Dysfunction in Hypercholesterolemia. Journal of the American College of Cardiology, 36, 103-109.
[23] Moghadasian, M.H., Frohlich, J.J. and McManus, B.M. (2001) Advances in Experimental Dyslipidemia and Atherosclerosis. Laboratory Investigation, 81, 1173-1183.
[24] Vilahur, G., Padro, T. and Badimon, L. (2011) Atherosclerosis and Thrombosis: Insights from Large Animal Models. Journal of Biomedicine and Biotechnology, 2011, Article ID: 907575.
[25] Busnelli, M., Froio, A., Bacci, M.L., Giunti, M., Cerrito, M.G., Giovannoni, R., et al. (2009) Pathogenetic Role of Hypercholesterolemia in a Novel Preclinical Model of Vascular Injury in Pigs. Atherosclerosis, 207, 384-390.
[26] Schaefer, E.J., Levy, R.I., Ernst, N.D., Van Sant, F.D. and Brewer Jr., H.B. (1981) The Effects of Low Cholesterol, High Polyunsaturated Fat, and Low Fat Diets on Plasma Lipid and Lipoprotein Cholesterol Levels in Normal and Hypercholesterolemic Subjects. American Journal of Clinical Nutrition, 34, 1758-1763.
[27] Ehnholm, C., Huttunen, J.K., Pietinen, P., Leino, U., Mutanen, M., Kostiainen, E., et al. (1982) Effect of Diet on Serum Lipoproteins in a Population with a High Risk of Coronary Heart Disease. New England Journal of Medicine, 307, 850-855. http://dx.doi.org/10.1056/NEJM198209303071403
[28] Sattler, K.J.E., Galili, O., Rodriguez-Porcel, M., Krier, J.D., Lerman, L.O. and Lerman, A. (2006) Dietary Reversal of Experimental Hypercholesterolemia Improves Endothelial Dysfunction of Epicardial Arteries but Not of Small Coronary Vessels in Pigs. Atherosclerosis, 188, 301-308. http://dx.doi.org/10.1016/j.atherosclerosis.2005.11.009
[29] Artinger, S., Deiner, C., Loddenkemper, C., Schwimmbeck, P.L., Schultheiss, H.P. and Pels, K. (2009) Complex Porcine Model of Atherosclerosis: Induction of Early Coronary Lesions after Long-Term Hyperlipidemia without Sustained Hyperglycemia. Canadian Journal of Cardiology, 25, e109-e114.
[30] Puccinelli, E., Gervasi, P.G., Trivella, M.G., et al. (2014) Modulation of Lipid Homeostasis in Response to Continuous or Intermittent High-Fat Diet in Pigs. Animal: An International Journal of Animal Bioscience.
[31] Stary, H.C., Chandler, A.B., Glagov, S., Guyton, J.R., Insull Jr., W., Rosenfeld, M.E., et al. (1994) A Definition of Initial, Fatty Streak, and Intermediate Lesions of Atherosclerosis. A Report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation, 89, 2462-2478.
[32] Friedewald, W.T., Levy, R.I. and Fredrickson, D.S. (1972) Estimation of the Concentration of Low-Density Lipoprotein Cholesterol in Plasma, without Use of the Preparative Ultracentrifuge. Clinical Chemistry, 18, 499-502.
[33] Franzini, M., Ottaviano, V., Fierabracci, V., Bramanti, E., Zyw, L., Barsacchi, R., et al. (2008) Fractions of Plasma Gamma-Glutamyltransferase in Healthy Individuals: Reference Values. Clinica Chimica Acta, 395, 188-189.
[34] Franzini, M., Bramanti, E., Ottaviano, V., Ghiri, E., Scatena, F., Barsacchi, R., et al. (2008) A High Performance Gel Filtration Chromatography Method for Gamma-Glutamyltransferase Fraction Analysis. Analytical Biochemistry, 374, 1-6.
[35] Stary, H.C. (2000) Natural History and Histological Classification of Atherosclerotic Lesions: An Update. Arteriosclerosis, Thrombosis, and Vascular Biology, 20, 1177-1178.
[36] Virmani, R., Kolodgie, F.D., Burke, A.P., Farb, A. and Schwartz, S.M. (2000) Lessons from Sudden Coronary Death: A Comprehensive Morphological Classification Scheme for Atherosclerotic Lesions. Arteriosclerosis, Thrombosis, and Vascular Biology, 20, 1262-1275.
[37] Matsuzawa-Nagata, N., Takamura, T., Ando, H., Nakamura, S., Kurita, S., Misu, H., et al. (2008) Increased Oxidative Stress Precedes the Onset of High-Fat Diet-Induced Insulin Resistance and Obesity. Metabolism-Clinical and Experimental, 57, 1071-1077.
[38] Schwab, D.A., Rea, T.J., Hanselman, J.C., Bisgaier, C.L., Krause, B.R. and Pape, M.E. (2000) Elevated Hepatic Apolipoprotein AI Transcription Is Associated with Diet-Induced Hyperalphalipoproteinemia in Rabbits. Life Sciences, 66, 1683-1694.
[39] Onat, A., Hergenç, G., Bulur, S., Ugur, M., Küçükdurmaz, Z. and Can, G. (2010) The Paradox of High Apolipoprotein A-I Levels Independently Predicting Incident Type-2 Diabetes among Turks. International Journal of Cardiology, 142, 72-79.
[40] Busnelli, M., Manzini, S., Froio, A., Vargiolu, A., Cerrito, M.G., Smolenski, R.T., et al. (2013) Diet Induced Mild Hypercholesterolemia in Pigs: Local and Systemic Inflammation, Effects on Vascular Injury—Rescue by High-Dose Statin Treatment. PLoS ONE, 8, e80588.
[41] Wilson, S.H., Simari, R.D., Best, P.J., Peterson, T.E., Lerman, L.O., Aviram, M., et al. (2001) Simvastatin Preserves Coronary Endothelial Function in Hypercholesterolemia in the Absence of Lipid Lowering. Arteriosclerosis, Thrombosis, and Vascular Biology, 21, 122-128.
[42] Puccinelli, E., Gervasi, P.G., Pelosi, G., Puntoni, M. and Longo, V. (2013) Modulation of Cytochrome P450 Enzymes in Response to Continuous or Intermittent High-Fat Diet in Pigs. Xenobiotica, 43, 686-698.
[43] Shrestha, C., Ito, T., Kawahara, K.I., Shrestha, B., Yamakuchi, M., Hashiguchi, T. and Maruyama, I. (2013) Saturated Fatty Acid Palmitate Induces Extracellular Release of Histone H3: A Possible Mechanistic Basis for High-Fat Diet-Induced Inflammation and Thrombosis. Biochemical and Biophysical Research Communications, 437, 573-578.
[44] Lin, H.L., Shen, K.P., Chang, W.T., Lin, J.C., An, L.M., Chen, I.J. and Wu, B.N. (2013) Eugenosedin—A Prevents High-Fat Diet Increased Adhesion Molecules through Inhibition of MAPK-and p65-Mediated NF-κB Pathway in Rat Model. Journal of Pharmacy and Pharmacology, 65, 300-309.
[45] Fotis, L., Agrogiannis, G., Vlachos, I.S., Pantopoulou, A., Margoni, A., Kostaki, M., et al. (2012) Intercellular Adhesion Molecule (ICAM)-1 and Vascular Cell Adhesion Molecule (VCAM)-1 at the Early Stages of Atherosclerosis in a Rat Model. In Vivo, 26, 243-250.
[46] Nofer, J.R., van der Giet, M., Tölle, M., Wolinska, I., von Wnuck Lipinski, K., Baba, H.A., et al. (2004) HDL Induces NO-Dependent Vasorelaxation via the Lysophospholipid Receptor S1P3. Journal of Clinical Investigation, 113, 569- 581.
[47] Spieker, L.E., Sudano, I., Hürlimann, D., Lerch, P.G., Lang, M.G., Binggeli, C., et al. (2002) High-Density Lipoprotein Restores Endothelial Function in Hypercholesterolemic Men. Circulation, 105, 1399-1402.
[48] Zanzinger, J. and Bassenge, E. (1993) Coronary Vasodilation to Acetylcholine, Adenosine and Bradykinin in Dogs: Effects of Inhibition of NO-Synthesis and Captopril. European Heart Journal, 14, 164-168.
[49] Smits, P., Williams, S.B., Lipson, D.E., Banitt, P., Rongen, G.A. and Creager, M.A. (1995) Endothelial Release of Nitric Oxide Contributes to the Vasodilator Effect of Adenosine in Humans. Circulation, 92, 2135-2141.
[50] Heaps, C.L., Tharp, D.L. and Bowles, D.K. (2004) Hypercholesterolemia Abolishes Voltage-Dependent K+ Channel Contribution to Adenosine-Mediated Relaxation in Porcine Coronary Arterioles. American Journal of Physiology: Heart and Circulatory Physiology, 288, H568-H576.
[51] Galderisi, M., Capaldo, B., Sidiropulos, M., D’Errico, A., Ferrara, L., Turco, A., et al. (2007) Determinants of Reduction of Coronary Flow Reserve in Patients with Type 2 Diabetes Mellitus or Arterial Hypertension without Angiographically Determined Epicardial Coronary Stenosis. American Journal of Hypertension, 20, 1283-1290.
[52] Gordon, D.J., Probstfield, J.L., Garrison, R.J., Neaton, J.D., Castelli, W.P., Knoke, J.D., et al. (1989) High-Density Lipoprotein Cholesterol and Cardiovascular Disease. Four Prospective American Studies. Circulation, 79, 8-15.
[53] Leroith, D. (2012) Pathophysiology of the Metabolic Syndrome: Implications for the Cardiometabolic Risks Associated With Type 2 Diabetes. The American Journal of the Medical Sciences, 343, 13-16.
[54] Nakou, E.S., Filippatos, T.D., Kiortsis, D.N., Derdemezis, C.S., Tselepis, A.D., Mikhailidis, D.P. and Elisaf, M.S. (2008) The Effects of Ezetimibe and Orlistat, Alone or in Combination, on High-Density Lipoprotein (HDL) Subclasses and HDL-Associated Enzyme Activities in Overweight and Obese Patients with Hyperlipidaemia. Expert Opinion on Pharmacotherapy, 9, 3151-3158.
[55] Filippatos, T.D., Liberopoulos, E.N., Kostapanos, M., Gazi, I.F., Papavasiliou, E.C., Kiortsis, D.N., Tselepis, A.D. and Elisaf, M.S. (2008) The Effects of Orlistat and Fenofibrate, Alone or in Combination, on High-Density Lipoprotein Subfractions and Pre-beta1-HDL Levels in Obese Patients with Metabolic Syndrome. Diabetes, Obesity and Metabolism, 10, 476-483.
[56] Wedel, H., McMurray, J.J., Lindberg, M., et al. (2009) Predictors of Fatal and Non-Fatal Outcomes in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA): Incremental Value of Apolipoprotein A-1, High-Sensi- tivity C-Reactive Peptide and N-Terminal Pro B-Type Natriuretic Peptide. European Journal of Heart Failure, 11, 281-291.
[57] Markel, A. (2011) The Resurgence of Niacin: From Nicotinic Acid to Niaspan/Laropiprant. Israel Medical Association Journal, 13, 368-374.
[58] Sirtori, C.R. (2011) Investigational CETP Antagonists for Hyperlipidemia and Atherosclerosis Prevention. Expert Opinion on Investigational Drugs, 20, 1543-1554.
[59] Chenevard, R., Hürlimann, D., Spieker, L., Béchir, M., Enseleit, F., Hermann, M., et al. (2010) Reconstituted HDL in Acute Coronary Syndromes. Cardiovascular Therapeutics, 30, e51-e57.
[60] Sherman, C.B., Peterson, S.J. and Frishman, W.H. (2010) Apolipoprotein A-I Mimetic Peptides: A Potential New Therapy for the Prevention of Atherosclerosis. Cardiology in Review, 18, 141-147.
[61] Stokes, K.Y., Cooper, D., Tailor, A. and Granger, D.N. (2002) Hypercholesterolemia Promotes Inflammation and Microvascular Dysfunction: Role of Nitric Oxide and Superoxide1. Free Radical Biology and Medicine, 33, 1026-1036.

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