Download PDF
Semin Thromb Hemost 2000; 26(5): 529-538
DOI: 10.1055/s-2000-13209
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Endothelial Dysfunction in Hypercholesterolemia: Mechanisms, Pathophysiological Importance, and Therapeutic Interventions

Ulf Landmesser, Burkhard Hornig, Helmut Drexler
  • Abteilung Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Germany
Further Information

Publication History

Publication Date:
31 December 2000 (online)

    Permissions and Reprints

ABSTRACT

Since the demonstration of the obligatory role of the endothelium in arterial relaxation by Furchgott and Zawadzki (1980), there has been great interest in the role of the endothelium in vascular disease. Apart from endothelium-dependent vasodilation, other important functions of the endothelium have now been studied, that is, the regulation of adhesion and infiltration of leukocytes and inhibition of platelet adhesion and aggregation. Many functions of the endothelium are influenced by nitric oxide (NO), which is synthesized by endothelial NO synthase. Endothelial dysfunction in hypercholesterolemic patients is in large part due to a reduced bioavailability of NO. Multiple factors contribute to this, including increased inactivation of NO by radicals and inhibition of NO formation by different mechanisms. The functional implications of endothelial dysfunction are not completely defined. However, recent studies suggest that endothelial dysfunction contributes to myocardial perfusion abnormalities. Furthermore, endothelial dysfunction may play an important role with respect to development and progression of atherosclerosis because the endothelium is involved in the regulation of key events of the atherosclerotic process. Endothelial dysfunction in hypercholesterolemia is reversible by cholesterol-lowering treatment, that is treatment with HMG-CoA-reductase inhibitors. First experimental data suggest that maneuvers that increase the bioavailability of NO in hypercholesterolemia may even result in regression of preexisting atherosclerotic lesions.

KEYWORD

Endothelium - nitric oxide - hypercholesterolemia - oxidative stress - atherosclerosis

REFERENCES

  • 1 Furchgott R F, Zawadski J V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.  Nature . 1980;  228 373-376
    PubMedGoogle Scholar
  • 2 Creager M A, Cooke J P, Mendelsohn M E. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans.  J Clin Invest . 1990;  86 228-234
    CrossrefPubMedGoogle Scholar
  • 3 Drexler H, Zeiher A M, Meinzer K. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolemic patients by L-arginine.  Lancet . 1991;  338 1546-1550
    CrossrefPubMedGoogle Scholar
  • 4 Drexler H, Zeiher A M. Endothelial function in human coronary arteries in vivo. Focus on hypercholsterolemia.  Hypertension . 1991;  18(4 Suppl) II90-99
    PubMedGoogle Scholar
  • 5 Chowienczyk P J, Watts G F, Cockgroft J R. Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholsterolaemia.  Lancet . 1992;  340 1430-1432
    CrossrefPubMedGoogle Scholar
  • 6 Zeiher A M, Drexler H, Wollschläger H. Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis.  Circulation . 1991;  83 391-401
    CrossrefPubMedGoogle Scholar
  • 7 Vita J A, Treasure C B, Nabel E G. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease.  Circulation . 1990;  81 491-497
    CrossrefPubMedGoogle Scholar
  • 8 Sorensen K E, Celermajer D S, Georgakopoulos D. Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein (a) level.  J Clin Invest . 1994;  93 50-55
    CrossrefPubMedGoogle Scholar
  • 9 Zeiher A M, Drexler H, Saurbier B. Endothelium-mediated coronary blood flow modulation in humans. Effects of age, atherosclerosis, hypercholesterolemia, and hypertension.  J Clin Invest . 1993;  92 652-662
    CrossrefPubMedGoogle Scholar
  • 10 Tall A R. Plasma high density lipoproteins. Metabolism and relationship to atherogenesis.  J Clin Invest . 1990;  86 379-384
    CrossrefPubMedGoogle Scholar
  • 11 Drexler H, Zeiher A M, Köster W. Endothelial dysfunction in the coronary circulation in hypercholsterolemia.  Circulation . 1992;  86(Suppl I) I-117
    PubMedGoogle Scholar
  • 12 Chowienczyk P J, Watts G F, Cockgroft J R. Sex differences in endothelial function in normal and hypercholesterolaemic subjects.  Lancet . 1994;  344 305-306
    CrossrefPubMedGoogle Scholar
  • 13 Keaney J F, Shwaery G T, Xu A. 17 Beta-estradiol preserves endothelial vasodilator function and limits low-density lipoprotein oxidation in hypercholesterolemic swine.  Circulation . 1994;  89 2251-2259
    PubMedGoogle Scholar
  • 14 Casino P R, Kilcoyne C M, Quyyumi A A. The role of nitric oxide in endothelium-dependent vasodilation of hypercholsterolemic patients.  Circulation . 1993;  88 2541-2547
    PubMedGoogle Scholar
  • 15 Quyyumi A A, Dakak N, Andrews N P. Nitric oxide activity in the human coronary circulation. Impact of risk factors for coronary atherosclerosis.  J Clin Invest . 1995;  95 1747-1755
    PubMedGoogle Scholar
  • 16 Quyyumi A A, Mulcahy D, Andrews N P. Coronary vascular nitric oxide activity in hypertension and hypercholsterolemia. Comparison of acetylcholine and substance P.  Circulation . 1997;  95 104-110
    PubMedGoogle Scholar
  • 17 Mügge A, Elwell J H, Peterson T E. Chronic treatment with polyethylene glycolated superoxide dismutase partially restores endothelium-dependent vascular relaxations in cholesterol-fed rabbits.  Circ Res . 1991;  69 1293-1300
    PubMedGoogle Scholar
  • 18 Keaney J F, Xu A, Cunningham D. Dietary probucol preserves endothelial function in cholesterol-fed rabbits by limiting vascular oxidative stress and superoxide generation.  J Clin Invest . 1995;  95 2520-2529
    PubMedGoogle Scholar
  • 19 Keaney J F, Gaziano J M, Xu Z. Dietary antioxidants preserve endothelium-dependent vessel relaxation in cholesterol-fed rabbits.  Proc Natl Acad Sci USA . 1993;  90 11880-11884
    PubMedGoogle Scholar
  • 20 Keaney J F, Gaziano J M, Xu Z. Low dose α-tocopherol improves and high dose α-tocopherol worsens endothelial vasodilator function in cholesterol-fed rabbits.  J Clin Invest . 1994;  93 844-851
    CrossrefPubMedGoogle Scholar
  • 21 Keaney J F, Guo Y, Cunningham D. Vascular incorporation of alpha-tocopherol prevents endothelial dysfunction due to oxidized LDL by inhibiting protein kinase C stimulation.  J Clin Invest . 1996;  98 386-394
    PubMedGoogle Scholar
  • 22 Ohara Y, Peterson T E, Harrison D G. Hypercholesterolemia increases endothelial superoxide anion production.  J Clin Invest . 1993;  91 2546-2551
    CrossrefPubMedGoogle Scholar
  • 23 Mügge A, Brandes R P, Böger R H. Vascular release of superoxide radicals is enhanced in hypercholsterolemic rabbits.  J Cardiovasc Pharmacol . 1994;  24 994-998
    PubMedGoogle Scholar
  • 24 Warnholtz A, Nickenig G, Schulz E. Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis: Evidence for involvement of the renin-angiotensin system.  Circulation . 1999;  99 2027-2033
    CrossrefPubMedGoogle Scholar
  • 25 Ting H H, Timimi F K, Haley E A. Vitamin C improves endothelium-dependent vasodilation in forearm resistance vessels of humans with hypercholesterolemia.  Circulation . 1997;  95 2617-2622
    PubMedGoogle Scholar
  • 26 Neunteufel T, Kostner K, Katzenschlager R. Additional benefit of vitamin E supplementation to simvastatin therapy on vasoreactivity of the brachial artery of hypercholesterolemic men.  J Am Coll Cardiol . 1998;  32 711-716
    CrossrefPubMedGoogle Scholar
  • 27 Huraux C, Makita T, Kurz S. Superoxide production, risk factors, and endothelium-dependent relaxations in human internal mammary arteries.  Circulation . 1999;  99 53-59
    PubMedGoogle Scholar
  • 28 Reilly M P, Pratico D, Delanty N. Increased formation of distinct F2 isoprostanes in hypercholesterolemia.  Circulation . 1998;  98 2822-2828
    CrossrefPubMedGoogle Scholar
  • 29 Heitzer T, Ylä-Herttuala S, Luoma J. Cigarette smoking potentiates endothelial dysfunction of forearm resistance vessels in patients with hypercholesterolemia: Role of oxidized LDL.  Circulation . 1996;  93 1346-1353
    CrossrefPubMedGoogle Scholar
  • 30 White C R, Darley-Usmar V, Berrington W R. Circulating plasma xanthine oxidase contributes to vascular dysfunction in hypercholesterolemic rabbits.  Proc Natl Acad Sci USA . 1996;  93 8745-8749
    CrossrefPubMedGoogle Scholar
  • 31 Cardillo C, Kilcoyne C M, Cannon R O. Xanthine oxidase inhibition with oxypurinol improves endothelial vasodilator function in hypercholesterolemic but not in hypertensive patients.  Hypertension . 1997;  30 57-63
    PubMedGoogle Scholar
  • 32 Pritchard K A, Groszek L, Smalley D M. Native low-densitiy lipoprotein increases endothelial cell nitric oxide synthase generation of superoxide anion.  Circ Res . 1995;  77 510-518
    PubMedGoogle Scholar
  • 33 Mollnau H, Hartmann M, Matheis E. HMG-CoA reductase inhibition normalizes endothelial dysfunction by inhibiting NADH oxidase activity and nitric oxide synthase mediated superoxide production in experimental hyperlipidemia.  Circulation . 1999;  100(Suppl I) I-621(Abst)
    PubMedGoogle Scholar
  • 34 Omar H A, Cherry P D, Mortelliti M P. Inhibition of coronary artery superoxide dismutase attenuates endothelium-dependent and independent nitrovasodilator relaxation.  Circ Res . 1991;  69 601-608
    PubMedGoogle Scholar
  • 35 Mügge A, Elwell J H, Peterson T E. Release of intact endothelium-derived relaxing factor depends on endothelial superoxide dismutase activity.  Am J Physiol . 1991;  260 C219-C225
    PubMedGoogle Scholar
  • 36 Lynch S M, Frei B, Morrow J D. Vascular superoxide dismutase deficiency impairs endothelial vasodilator function through direct inactivation of nitric oxide and increased lipid peroxidation.  Arterioscler Thromb Vasc Biol . 1997;  17 2975-2981
    PubMedGoogle Scholar
  • 37 Stralin P, Karlsson K, Johansson B O. The interstitium of the human arterial wall contains very large amounts of extracellular superoxide dismutase.  Arterioscler Thromb Vasc Biol . 1995;  15 2032-2036
    PubMedGoogle Scholar
  • 38 Landmesser U, Hornig B, Merten R. Vascular extracellular superoxide dismutase activity in patients with coronary artery disease: Relation to endothelium-dependent vasodilation.  Circulation . 2000;  101 2264-2270
    CrossrefPubMedGoogle Scholar
  • 39 Fukai T, Galis Z S, Meng X P. Vascular expression of extracellular superoxide dismutase in atherosclerosis.  J Clin Invest . 1998;  101 2101-2111
    PubMedGoogle Scholar
  • 40 Bode-Böger S M, Böger R H, Kienke S. Elevated L-arginine/dimethylarginine ratio contributes to enhanced systemic NO production by dietary L-arginine in hypercholesterolemic rabbits.  Biochem Biophys Res Commun . 1996;  219 598-603
    CrossrefPubMedGoogle Scholar
  • 41 Böger R H, Bode-Böger S M, Szuba A. Assymetric dimethylarginine (ADMA): A novel risk factor for endothelial dysfunction. Its role in hypercholesterolemia.  Circulation . 1998;  98 1842-1847
    PubMedGoogle Scholar
  • 42 Creager M A, Gallagher S J, Girerd X J. L-Arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans.  J Clin Invest . 1992;  90 1248-1253
    PubMedGoogle Scholar
  • 43 Clarkson P, Adams M R, Powe A J. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults.  J Clin Invest . 1996;  97 1989-1994
    CrossrefPubMedGoogle Scholar
  • 44 Ito A, Tsao P S, Adimoolam S. Novel mechansim for endothelial dysfunction: Dysregulation of dimethylarginine dimethylaminohydrolase.  Circulation . 1999;  99 3092-3095
    CrossrefPubMedGoogle Scholar
  • 45 Stroes E, Kastelein J, Cosentino F. Tetrahydrobiopterin restores endothelial function in hypercholesterolemia.  J Clin Invest . 1997;  99 41-46
    CrossrefPubMedGoogle Scholar
  • 46 Xia Y, Tsai A L, Berka V. Superoxide generation from endothelial nitric-oxide synthase.  A Ca2+/calmodulin-dependent and tetrahydrobiopterin regulatory process. J Biol Chem . 1998;  273 25804-25808
    CrossrefPubMedGoogle Scholar
  • 47 Michel T, Feron O. Nitric oxide synthases: Which, where, how, and why?.  J Clin Invest . 1997;  100 2146-2152
    CrossrefPubMedGoogle Scholar
  • 48 Feron O, Saldana F, Michel J B. The endothelial nitric-oxide synthase-caveolin regulatory cycle.  J Biol Chem . 1998;  273 3125-3128
    CrossrefPubMedGoogle Scholar
  • 49 Feron O, Dessy C, Moniotte S. Hypercholesterinemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase.  J Clin Invest . 1999;  103 897-905
    PubMedGoogle Scholar
  • 50 Best P, McKenna C, Hadai D. Chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia.  Circulation . 1999;  99 1747-1752
    PubMedGoogle Scholar
  • 51 Baller D, Gunawan N, Gleichmann U. Improvement in coronary flow reserve determined by positron emission tomography after 6 months of cholesterol-lowering therapy in patients with early stages of coronary atherosclerosis.  Circulation . 1999;  99 2871-2875
    PubMedGoogle Scholar
  • 52 Yokoyama I, Momomura S, Ohtake T. Improvement of impaired myocardial vasodilation due to diffuse coronary atherosclerosis in hypercholesterolemics after lipid-lowering therapy.  Circulation . 1999;  100 117-122
    PubMedGoogle Scholar
  • 53 Gould K L, Martucci J P, Goldberg D I. Short-term cholesterol lowering decreases size and severity of perfusion abnormalities by positron emission tomography after dipiridamol in patients with coronary artery disease: A potential noninvasive marker of healing coronary endothelium.  Circulation . 1994;  89 1530-1538
    PubMedGoogle Scholar
  • 54 Tsao P S, McEvoy L M, Drexler H. Enhanced endothelial adhesiveness in hypercholesterolemia is attenuated by L-arginine.  Circulation . 1994;  89 2176-2182
    PubMedGoogle Scholar
  • 55 Theilmeier G, Chan J R, Zalpour C. Adhesiveness of mononuclear cells in hypercholesterolemic humans is normalized by dietary L-arginine.  Arterioscler Thromb Vasc Biol . 1997;  17 3557-3564
    PubMedGoogle Scholar
  • 56 Qian H, Neplioueva V, Shetty G A. Nitric oxide synthase gene therapy rapidly reduced adhesion molecule expression and inflammatory cell infiltration in carotid arteries of cholesterol-fed rabbits.  Circulation . 1999;  99 2979-2982
    PubMedGoogle Scholar
  • 57 Zeiher A M, Fisslthaler B, Schray-Utz B. Nitric oxide modulates the expression of monocyte chemoattractant protein 1 in cultured human endothelial cells.  Circ Res . 1995;  76 980-986
    PubMedGoogle Scholar
  • 58 Tsao P S, Wang B, Buitrago R. Nitric oxide regulates monocyte chemotactic protein-1.  Circulation . 1997;  96 934-940
    PubMedGoogle Scholar
  • 59 Cooke J P, Singer A H, Tsao P S. Anti-atherogenic effects of L-arginine in the hypercholesterolemic rabbit.  J Clin Invest . 1992;  90 1168-1172
    CrossrefPubMedGoogle Scholar
  • 60 Wang B Y, Singer A H, Tsao P S. Dietary arginine prevents atherogenesis in the coronary artery of the hypercholesterolemic rabbit.  J Am Coll Cardiol . 1994;  23 452-458
    PubMedGoogle Scholar
  • 61 Aji W, Ravalli S, Szabolcs M. L-Arginine prevents xanthoma development and inhibits atherosclerosis in LDL receptor knock out mice.  Circulation . 1997;  95 430-437
    PubMedGoogle Scholar
  • 62 Cayatte A J, Palacine J J, Horten K. Chronic inhibition of nitric oxide production accelerates neointima formation and impairs endothelial function in hypercholesterolemic rabbits.  Arterioscler Thromb . 1994;  14 753-759
    CrossrefPubMedGoogle Scholar
  • 63 Candipan R C, Wang B Y, Buitrago R. Regression or progression. Dependency on vascular nitric oxide.  Arterioscler Thromb Vasc Biol . 1996;  16 44-50
    PubMedGoogle Scholar
  • 64 Wang B Y, Ho H K, Lin P S. Regression of atherosclerosis: Role of nitric oxide and apoptosis.  Circulation . 1999;  99 1236-1241
    PubMedGoogle Scholar
  • 65 Tsao P, Theilmeier G, Singer A. L-Arginine attenuates platelet reactivity in hypercholesterolemic rabbits.  Arterioscler Thromb . 1994;  14 1529-1533
    PubMedGoogle Scholar
  • 66 Wolf A, Zalpour C, Theilmeier G. Dietary L-arginine supplementation normalizes platelet aggregation in hypercholesterolemic humans.  J Am Coll Cardiol . 1997;  29 479-485
    CrossrefPubMedGoogle Scholar
  • 67 Harrison D G, Armstrong M L, Freiman P C. Restoration of endothelium-dependent relaxation by dietary treatment of atherosclerosis.  J Clin Invest . 1987;  80 1808-1811
    PubMedGoogle Scholar
  • 68 Leung W, Lau C, Wong C. Beneficial effect of cholesterol-lowering therapy on coronary endothelium-dependent relaxation in hypercholesterolemic patients.  Lancet . 1993;  341 1496-1500
    CrossrefPubMedGoogle Scholar
  • 69 Egashira K, Kirooka Y, Kai H. Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia.  Circulation . 1994;  89 2519-2524
    PubMedGoogle Scholar
  • 70 O'Discroll G, Green D, Taylor R R. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month.  Circulation . 1997;  95 1126-1131
    PubMedGoogle Scholar
  • 71 John S, Schlaich M, Langenfeld M. Increased bioavailability of nitric oxide after lipid lowering therapy in hypercholesterolemic patients: A randomized, placebo-controlled, double-blind study.  Circulation . 1998;  98 211-216
    PubMedGoogle Scholar
  • 72 Tamai O, Matsuoka H, Itabe H. Single LDL apheresis improves endothelium-dependent vasodilation in hypercholesterolemic humans.  Circulation . 1997;  95 76-82
    PubMedGoogle Scholar
  • 73 Laufs U, Fata V, Plutzky J. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors.  Circulation . 1998;  97 1129-1135
    CrossrefPubMedGoogle Scholar
  • 74 Nickenig G, Bäumer A T, Temur Y. Statin-sensitive dysregulated AT1 receptor function and density in hypercholesterolemic men.  Circulation . 1999;  100 2131-2134
    CrossrefPubMedGoogle Scholar
  • 75 Anderson T, Meredith I, Yeung A. The effect of cholesterol lowering and antioxidant therapy on endothelium-dependent coronary vasomotion.  N Engl J Med . 1995;  332 488-493
    CrossrefPubMedGoogle Scholar
  • 76 Becker R H, Wiemer G, Linz W. Preservation of endothelial function by ramipril in rabbits on a long-term atherogenic diet.  J Cardiovasc Pharmacol . 1991;  18(Suppl 2) S110-S115
    PubMedGoogle Scholar
  • 77 Hernandez A, Barberi L, Ballerio R. Delapril slows the progression of atherosclerosis and maintains endothelial function in cholesterol-fed rabbits.  Atherosclerosis . 1998;  137 71-76
    CrossrefPubMedGoogle Scholar
  • 78 Chobanian A V, Haudenschild C, Nickerson C. Antiatherogenic effect of captopril in the Watanabe heritable hyperlipidemic rabbit.  Hypertension . 1990;  15 327-331
    PubMedGoogle Scholar
  • 79 Schuh J R, Blehm D, Friedrich G. Differential effects of renin-angiotensin system blockade on atherogenesis in cholesterol-fed rabbits.  J Clin Invest . 1993;  91 1453-1458
    PubMedGoogle Scholar
  • 80 Keidar S, Attias J, Smith J. The angiotensin-II receptor antagonist, losartan, inhibits LDL lipid peroxidation and atherosclerosis in apolipoprotein E-deficient mice.  Biochem Biophys Res Commun . 1997;  236 622-625
    CrossrefPubMedGoogle Scholar
  • 81 Chobanian A V, Hope S, Brecher P. Dissociation between the antiatherosclerotic effect of trandopril and suppression of serum and aortic angiotensin-converting enzyme activity in the Watanabe heritable hyperlipidemic rabbit.  Hypertension . 1995;  25 1306-1310
    PubMedGoogle Scholar
  • 82 Hope S, Brecher P, Chobanian A V. Comparison of the effects of AT1 receptor blockade and angiotensin converting enzyme inhibition on atherosclerosis.  Am J Hypertens . 1999;  12 28-34
    PubMedGoogle Scholar
  • 83 Miyazaki M, Sakonjo H, Takai S. Anti-atherosclerotic effects of an angiotensin converting enzyme inhibitor and an angiotensin II antagonist in cynomolgus monkeys fed high cholesterol diet.  Br J Pharmacol . 1999;  128 523-529
    CrossrefPubMedGoogle Scholar
  • 84 Verhaar M C, Wever R M, Kastelein J J. 5-Methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia.  Circulation . 1998;  97 237-241
    PubMedGoogle Scholar
  • 85 Verhaar M C, Wever R M, Kastelein J J. Effects of oral folic acid supplemetation on endothelial function in familial hypercholesterolemia. A randomized placebo-controlled trial.  Circulation . 1999;  100 335-338
    PubMedGoogle Scholar
  • 86 Alexander R W. Hypertension and the pathogenesis of atherosclerosis: Oxidative stress and the mediation of arterial inflammatory response: A new perspective.  Hypertension . 1995;  25 155-161
    PubMedGoogle Scholar
  • 87 Kunsch C, Medford R M. Oxidative stress as a regulator of gene expression in the vasculature.  Circ Res . 1999;  85 753-766
    PubMedGoogle Scholar
  • 88 Cooke J P, Tsao P S. Arginine: A new therapy for atherosclerosis?.  Circulation . 1997;  95 311-312
    PubMedGoogle Scholar
      >