Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1017-1022
© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Mechanism of Endothelial Dysfunction in Apolipoprotein E–Deficient Mice
From the Departments of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic and Foundation, Rochester, Minn.
Correspondence to Zvonimir S. Katusic, MD, PhD, Department of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail katusic.zvonimir{at}mayo.edu
Abstract—Endothelium-dependent relaxations mediated by NO are impaired in a mouse model of human atherosclerosis. Our objective was to characterize the mechanisms underlying endothelial dysfunction in aortas of apolipoprotein E (apoE)-deficient mice, treated for 26 to 29 weeks with a lipid-rich Western-type diet. Aortic rings from apoE-deficient mice showed impaired endothelium-dependent relaxations to acetylcholine (10-9 to 10-5 mol/L) and Ca2+ ionophore (10-9 to 10-6 mol/L) and endothelium-independent relaxations to diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA-NONOate, 10-10 to 10-5 mol/L) compared with aortic rings from C57BL/6J mice (P<0.05). By use of confocal microscopy of an oxidative fluorescent probe (dihydroethidium), increased superoxide anion (O2-) production was demonstrated throughout the aortic wall but mainly in smooth muscle cells of apoE-deficient mice. CuZn–superoxide dismutase (SOD) and Mn-SOD protein expressions were unaltered in the aorta exposed to hypercholesterolemia. A cell-permeable SOD mimetic, Mn(III) tetra(4-benzoic acid) porphyrin chloride (10-5 mol/L), reduced O2- production and partially normalized relaxations to acetylcholine and DEA-NONOate in apoE-deficient mice (P<0.05). [14C]L-Citrulline assay showed a decrease of Ca2+-dependent NOS activity in aortas from apoE-deficient mice compared with C57BL/6J mice (P<0.05), whereas NO synthase protein expression was unchanged. In addition, cGMP levels were significantly reduced in the aortas of apoE-deficient mice (P<0.05). Our results demonstrate that in apoE-deficient mice on a Western-type fat diet, impairment of endothelial function is caused by increased production of O2- and reduced endothelial NO synthase enzyme activity. Thus, chemical inactivation of NO with O2- and reduced biosynthesis of NO are key mechanisms responsible for endothelial dysfunction in aortas of atherosclerotic apoE-deficient mice.
Key Words: endothelium • nitric oxide • superoxide anion • apolipoprotein E • atherosclerosis
This article has been cited by other articles:
 |
|
 |
|
  D. Nam, C.-W. Ni, A. Rezvan, J. Suo, K. Budzyn, A. Llanos, D. Harrison, D. Giddens, and H. Jo Partial carotid ligation is a model of acutely induced disturbed flow, leading to rapid endothelial dysfunction and atherosclerosis Am J Physiol Heart Circ Physiol, October 1, 2009; 297(4): H1535 - H1543. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Ponnuswamy, E. Ostermeier, A. Schrottle, J. Chen, P. L. Huang, G. Ertl, B. Nieswandt, and P. J. Kuhlencordt Oxidative Stress and Compartment of Gene Expression Determine Proatherosclerotic Effects of Inducible Nitric Oxide Synthase Am. J. Pathol., June 1, 2009; 174(6): 2400 - 2410. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-L. Liu, Y.-H. Li, G.-Y. Shi, S.-H. Tang, S.-J. Jiang, C.-W. Huang, P.-Y. Liu, J.-S. Hong, and H.-L. Wu Dextromethorphan reduces oxidative stress and inhibits atherosclerosis and neointima formation in mice Cardiovasc Res, April 1, 2009; 82(1): 161 - 169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Moukdar, J. Robidoux, O. Lyght, J. Pi, K. W. Daniel, and S. Collins Reduced antioxidant capacity and diet-induced atherosclerosis in uncoupling protein-2-deficient mice J. Lipid Res., January 1, 2009; 50(1): 59 - 70. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Hazarika, M. Angelo, Y. Li, A. J. Aldrich, S. I. Odronic, Z. Yan, J. S. Stamler, and B. H. Annex Myocyte Specific Overexpression of Myoglobin Impairs Angiogenesis After Hind-Limb Ischemia Arterioscler Thromb Vasc Biol, December 1, 2008; 28(12): 2144 - 2150. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Alexander, M. E. Kerr, J. Balzer, M. Horowitz, A. Kassam, Y. Kim, L. Hoffman, and Y. P. Conley Cerebrospinal Fluid Apolipoprotein E, Calcium and Cerebral Vasospasm after Subarachnoid Hemorrhage Biol Res Nurs, October 1, 2008; 10(2): 102 - 112. [Abstract] [PDF]
|
|
|
|
|
|
A. P. C. Davel, L. E. Fukuda, L. L. De Sa, C. D. Munhoz, C. Scavone, D. Sanz-Rosa, V. Cachofeiro, V. Lahera, and L. V. Rossoni Effects of isoproterenol treatment for 7 days on inflammatory mediators in the rat aorta Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H211 - H219. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Wolfort, K. Y. Stokes, and D. N. Granger CD4+ T lymphocytes mediate hypercholesterolemia-induced endothelial dysfunction via a NAD(P)H oxidase-dependent mechanism Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2619 - H2626. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Vinh, R. E. Widdop, G. R. Drummond, and T. A. Gaspari Chronic angiotensin IV treatment reverses endothelial dysfunction in ApoE-deficient mice Cardiovasc Res, January 1, 2008; 77(1): 178 - 187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Nath, L. V. d'Uscio, J. P. Juncos, A. J. Croatt, M. C. Manriquez, S. T. Pittock, and Z. S. Katusic An analysis of the DOCA-salt model of hypertension in HO-1-/- mice and the Gunn rat Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H333 - H342. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Kitayama, F. M. Faraci, S. R. Lentz, and D. D. Heistad Cerebral Vascular Dysfunction During Hypercholesterolemia Stroke, July 1, 2007; 38(7): 2136 - 2141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Hattori, S. Hattori, X. Wang, H. Satoh, N. Nakanishi, and K. Kasai Oral Administration of Tetrahydrobiopterin Slows the Progression of Atherosclerosis in Apolipoprotein E-Knockout Mice Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 865 - 870. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Zhang, Y. Luo, W. Zhang, Y. He, S. Dai, R. Zhang, Y. Huang, P. Bernatchez, F. J. Giordano, G. Shadel, et al. Endothelial-Specific Expression of Mitochondrial Thioredoxin Improves Endothelial Cell Function and Reduces Atherosclerotic Lesions Am. J. Pathol., March 1, 2007; 170(3): 1108 - 1120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Matsumoto, D. J. Baker, L. V. d'Uscio, G. Mozammel, Z. S. Katusic, and J. M. van Deursen Aging-Associated Vascular Phenotype in Mutant Mice With Low Levels of BubR1 Stroke, March 1, 2007; 38(3): 1050 - 1056. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. C. Kane, C.-F. Lam, F. O'Cochlain, D. M. Hodgson, S. Reyes, X.-K. Liu, T. Miki, S. Seino, Z. S. Katusic, and A. Terzic Gene knockout of the KCNJ8-encoded Kir6.1 KATP channel imparts fatal susceptibility to endotoxemia FASEB J, November 1, 2006; 20(13): 2271 - 2280. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ohashi, M. S. Runge, F. M. Faraci, and D. D. Heistad MnSOD Deficiency Increases Endothelial Dysfunction in ApoE-Deficient Mice Arterioscler Thromb Vasc Biol, October 1, 2006; 26(10): 2331 - 2336. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Lorkowska, M. Bartus, M. Franczyk, R. B. Kostogrys, J. Jawien, P. M. Pisulewski, and S. Chlopicki Hypercholesterolemia Does Not Alter Endothelial Function in Spontaneously Hypertensive Rats J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1019 - 1026. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. V. d'Uscio and Z. S. Katusic Increased vascular biosynthesis of tetrahydrobiopterin in apolipoprotein E-deficient mice Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2466 - H2471. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Yang and X.-F. Ming Recent advances in understanding endothelial dysfunction in atherosclerosis. Clin. Med. Res., March 1, 2006; 4(1): 53 - 65. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Godfraind Antioxidant effects and the therapeutic mode of action of calcium channel blockers in hypertension and atherosclerosis Phil Trans R Soc B, December 29, 2005; 360(1464): 2259 - 2272. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-F. Lam, T. E. Peterson, A. J. Croatt, K. A. Nath, and Z. S. Katusic Functional adaptation and remodeling of pulmonary artery in flow-induced pulmonary hypertension Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2334 - H2341. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Kyselovic, P. Martinka, Z. Batova, A. Gazova, and T. Godfraind Calcium Channel Blocker Inhibits Western-Type Diet-Evoked Atherosclerosis Development in ApoE-Deficient Mice J. Pharmacol. Exp. Ther., October 1, 2005; 315(1): 320 - 328. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Dworschak, L. V. d'Uscio, D. Breukelmann, and J. D. Hannon Increased tolerance to hypoxic metabolic inhibition and reoxygenation of cardiomyocytes from apolipoprotein E-deficient mice Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H160 - H167. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Racasan, B. Braam, H. A. Koomans, and J. A. Joles Programming blood pressure in adult SHR by shifting perinatal balance of NO and reactive oxygen species toward NO: the inverted Barker phenomenon Am J Physiol Renal Physiol, April 1, 2005; 288(4): F626 - F636. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. B. Anning, B. Coles, A. Bermudez-Fajardo, P. E.M. Martin, B. S. Levison, S. L. Hazen, C. D. Funk, H. Kuhn, and V. B. O'Donnell Elevated Endothelial Nitric Oxide Bioactivity and Resistance to Angiotensin-Dependent Hypertension in 12/15-Lipoxygenase Knockout Mice Am. J. Pathol., March 1, 2005; 166(3): 653 - 662. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Suda, L. A. Smith, L. V. d'Uscio, T. E. Peterson, and Z. S. Katusic In Vivo Expression of Recombinant Vascular Endothelial Growth Factor in Rabbit Carotid Artery Increases Production of Superoxide Anion Arterioscler Thromb Vasc Biol, March 1, 2005; 25(3): 506 - 511. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Pflueger, A. J. Croatt, T. E. Peterson, L. A. Smith, L. V. d'Uscio, Z. S. Katusic, and K. A. Nath The hyperbilirubinemic Gunn rat is resistant to the pressor effects of angiotensin II Am J Physiol Renal Physiol, March 1, 2005; 288(3): F552 - F558. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-F. Ming, C. Barandier, H. Viswambharan, B. R. Kwak, F. Mach, L. Mazzolai, D. Hayoz, J. Ruffieux, S. Rusconi, J.-P. Montani, et al. Thrombin Stimulates Human Endothelial Arginase Enzymatic Activity via RhoA/ROCK Pathway: Implications for Atherosclerotic Endothelial Dysfunction Circulation, December 14, 2004; 110(24): 3708 - 3714. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. J. Alp, M. A. McAteer, J. Khoo, R. P. Choudhury, and K. M. Channon Increased Endothelial Tetrahydrobiopterin Synthesis by Targeted Transgenic GTP-Cyclohydrolase I Overexpression Reduces Endothelial Dysfunction and Atherosclerosis in ApoE-Knockout Mice Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 445 - 450. [Abstract] [Full Text]
|
|
|
|
|
|
C.-L. M Cooke and S. T Davidge Endothelial-dependent vasodilation is reduced in mesenteric arteries from superoxide dismutase knockout mice Cardiovasc Res, December 1, 2003; 60(3): 635 - 642. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A.C. 't Hoen, C. A.C. Van der Lans, M. Van Eck, M. K. Bijsterbosch, T. J.C. Van Berkel, and J. Twisk Aorta of ApoE-Deficient Mice Responds to Atherogenic Stimuli by a Prelesional Increase and Subsequent Decrease in the Expression of Antioxidant Enzymes Circ. Res., August 8, 2003; 93(3): 262 - 269. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. L. Tsakadze, S. Srivastava, S. O. Awe, A. S. O. Adeagbo, A. Bhatnagar, and S. E. D'Souza Acrolein-induced vasomotor responses of rat aorta Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H727 - H734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. Crauwels, C. E. Van Hove, P. Holvoet, A. G. Herman, and H. Bult Plaque-associated endothelial dysfunction in apolipoprotein E-deficient mice on a regular diet. Effect of human apolipoprotein AI Cardiovasc Res, July 1, 2003; 59(1): 189 - 199. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. V. d'Uscio, S. Milstien, D. Richardson, L. Smith, and Z. S. Katusic Long-Term Vitamin C Treatment Increases Vascular Tetrahydrobiopterin Levels and Nitric Oxide Synthase Activity Circ. Res., January 10, 2003; 92(1): 88 - 95. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Chen, P. Kuhlencordt, F. Urano, H. Ichinose, J. Astern, and P. L. Huang L-Arginine on Atherosclerosis in ApoE Knockout and ApoE/Inducible NO Synthase Double-Knockout Mice Arterioscler Thromb Vasc Biol, January 1, 2003; 23(1): 97 - 103. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. van Haperen, M. de Waard, E. van Deel, B. Mees, M. Kutryk, T. van Aken, J. Hamming, F. Grosveld, D. J. Duncker, and R. de Crom Reduction of Blood Pressure, Plasma Cholesterol, and Atherosclerosis by Elevated Endothelial Nitric Oxide J. Biol. Chem., December 6, 2002; 277(50): 48803 - 48807. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Munzel, I. B. Afanas'ev, A. L. Kleschyov, and D. G. Harrison Detection of Superoxide in Vascular Tissue Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1761 - 1768. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Maier and P. H. Chan Book Review: Role of Superoxide Dismutases in Oxidative Damage and Neurodegenerative Disorders Neuroscientist, August 1, 2002; 8(4): 323 - 334. [Abstract] [PDF]
|
|
|
|
|
|
L. V d'Uscio, M. Barton, S. Shaw, and T. F Luscher Chronic ETA receptor blockade prevents endothelial dysfunction of small arteries in apolipoprotein E-deficient mice Cardiovasc Res, February 1, 2002; 53(2): 487 - 495. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Bagi, Z. Ungvari, and A. Koller Xanthine Oxidase-Derived Reactive Oxygen Species Convert Flow-Induced Arteriolar Dilation to Constriction in Hyperhomocysteinemia: Possible Role of Peroxynitrite Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 28 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Boulanger, A. Scoazec, T. Ebrahimian, P. Henry, E. Mathieu, A. Tedgui, and Z. Mallat Circulating Microparticles From Patients With Myocardial Infarction Cause Endothelial Dysfunction Circulation, November 27, 2001; 104(22): 2649 - 2652. [Abstract] [Full Text] [PDF]
|
|