Circulation Research. 2001;88:756-762
doi: 10.1161/hh0801.089861
doi: 10.1161/hh0801.089861
© 2001 American Heart Association, Inc.
Reviews |
Nitric Oxide Insufficiency, Platelet Activation, and Arterial Thrombosis
From the Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Mass.
Correspondence to Joseph Loscalzo, MD, PhD, Department of Medicine, Boston University School of Medicine, 88 East Newton St, Boston, MA 02118-2394. E-mail jloscalz{at}bu.edu
Abstract—Nitric oxide (NO) was originally discovered as a vasodilator product of the endothelium. Over the last 15 years, this vascular mediator has been shown to have important antiplatelet actions as well. By activating guanylyl cyclase, inhibiting phosphoinositide 3-kinase, impairing capacitative calcium influx, and inhibiting cyclooxygenase-1, endothelial NO limits platelet activation, adhesion, and aggregation. Platelets are also an important source of NO, and this platelet-derived NO pool limits recruitment of platelets to the platelet-rich thrombus. A deficiency of bioactive NO is associated with arterial thrombosis in animal models, individuals with endothelial dysfunction, and patients with a deficiency of the extracellular antioxidant enzyme glutathione peroxidase-3. This enzyme catalyzes the reduction of hydrogen and lipid peroxides, which limits the availability of these reactive oxygen species to react with and inactivate NO. The complex biochemical reactions that underlie the function and inactivation of NO in the vasculature represent an important set of targets for therapeutic intervention for the prevention and treatment of arterial thrombotic disorders.
Key Words: endothelium • nitroglycerin • S-nitrosothiols • nitric oxide synthase • oxidative stress
This article has been cited by other articles:
 |
|
 |
|
  A. R. Asif, M. Hecker, and M. Cattaruzza Disinhibition of SOD-2 Expression to Compensate for a Genetically Determined NO Deficit in Endothelial Cells-Brief Report Arterioscler Thromb Vasc Biol, November 1, 2009; 29(11): 1890 - 1893. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. HRACSKO, E. HERMESZ, A. FERENCZ, H. ORVOS, Z. NOVAK, A. PAL, and I. S. VARGA Endothelial Nitric Oxide Synthase Is Up-regulated in the Umbilical Cord in Pregnancies Complicated with Intrauterine Growth Retardation In Vivo, September 1, 2009; 23(5): 727 - 732. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Sugiyama, B. D. Levy, and T. Michel Tetrahydrobiopterin Recycling, a Key Determinant of Endothelial Nitric-oxide Synthase-dependent Signaling Pathways in Cultured Vascular Endothelial Cells J. Biol. Chem., May 8, 2009; 284(19): 12691 - 12700. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Igarashi and T. Michel Sphingosine-1-phosphate and modulation of vascular tone Cardiovasc Res, May 1, 2009; 82(2): 212 - 220. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Chen, I-C. Peng, W. Sun, M.-I Su, P.-H. Hsu, Y. Fu, Y. Zhu, K. DeFea, S. Pan, M.-D. Tsai, et al. AMP-Activated Protein Kinase Functionally Phosphorylates Endothelial Nitric Oxide Synthase Ser633 Circ. Res., February 27, 2009; 104(4): 496 - 505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Castelli, L. Bergamaschini, P. Sailis, G. Pantaleo, and F. Porro The Impact of an Aging Population on the Diagnosis of Pulmonary Embolism: Comparison of Young and Elderly Patients Clinical and Applied Thrombosis/Hemostasis, February 1, 2009; 15(1): 65 - 72. [Abstract] [PDF]
|
|
|
|
|
|
M. Magnone, G. Basile, D. Bruzzese, L. Guida, M. G. Signorello, M. P. Chothi, S. Bruzzone, E. Millo, A.-D. Qi, R. A. Nicholas, et al. Adenylic Dinucleotides Produced by CD38 Are Negative Endogenous Modulators of Platelet Aggregation J. Biol. Chem., September 5, 2008; 283(36): 24460 - 24468. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. W. Fossum, B. Olszewska-Pazdrak, M. M. Mertens, L. A. Makarski, M. W. Miller, T. W. Hein, L. Kuo, F. Clubb, G. M. Fuller, and D. H. Carney TP508 (Chrysalin(R)) Reverses Endothelial Dysfunction and Increases Perfusion and Myocardial Function in Hearts With Chronic Ischemia Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2008; 13(3): 214 - 225. [Abstract] [PDF]
|
|
|
|
|
|
T. Thum and J. Borlak LOX-1 Receptor Blockade Abrogates oxLDL-induced Oxidative DNA Damage and Prevents Activation of the Transcriptional Repressor Oct-1 in Human Coronary Arterial Endothelium J. Biol. Chem., July 11, 2008; 283(28): 19456 - 19464. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. N. Morrell, H. Sun, M. Ikeda, J.-C. Beique, A. M. Swaim, E. Mason, T. V. Martin, L. E. Thompson, O. Gozen, D. Ampagoomian, et al. Glutamate mediates platelet activation through the AMPA receptor J. Exp. Med., March 17, 2008; 205(3): 575 - 584. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Webb, N. Patel, S. Loukogeorgakis, M. Okorie, Z. Aboud, S. Misra, R. Rashid, P. Miall, J. Deanfield, N. Benjamin, et al. Acute Blood Pressure Lowering, Vasoprotective, and Antiplatelet Properties of Dietary Nitrate via Bioconversion to Nitrite Hypertension, March 1, 2008; 51(3): 784 - 790. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Kim, S. Y. Suh, C. U. Choi, J. O. Na, E. J. Kim, S.-W. Rha, C. G. Park, H. S. Seo, and D. J. Oh Six-month comparison of coronary endothelial dysfunction associated with sirolimus-eluting stent versus Paclitaxel-eluting stent. J. Am. Coll. Cardiol. Intv., February 1, 2008; 1(1): 65 - 71. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. V. Mohan, I. A. Jagroop, D. P. Mikhailidis, and G. P. Stansby Homocysteine Activates Platelets In Vitro Clinical and Applied Thrombosis/Hemostasis, January 1, 2008; 14(1): 8 - 18. [Abstract] [PDF]
|
|
|
|
 |
|
 C. J. Glueck, R. A. Freiberg, J. Oghene, R. N. Fontaine, and P. Wang Association Between the T-786C eNOS Polymorphism and Idiopathic Osteonecrosis of the Head of the Femur J. Bone Joint Surg. Am., November 1, 2007; 89(11): 2460 - 2468. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Letts and J. Loscalzo Frontiers in Nephrology: Targeting Inflammation Using Novel Nitric Oxide Donors J. Am. Soc. Nephrol., November 1, 2007; 18(11): 2863 - 2869. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Villagra, S. Shiva, L. A. Hunter, R. F. Machado, M. T. Gladwin, and G. J. Kato Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin Blood, September 15, 2007; 110(6): 2166 - 2172. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.-a. Okabe, K. Shimada, M. Hattori, T. Murayama, M. Yokode, T. Kita, and C. Kishimoto Swimming reduces the severity of atherosclerosis in apolipoprotein E deficient mice by antioxidant effects Cardiovasc Res, June 1, 2007; 74(3): 537 - 545. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. C. Fagan, H. F. Elewa, and D. J. Rychly Statin Therapy for Secondary Stroke Prevention: Evidence Catches Up to Practice Journal of Pharmacy Practice, April 1, 2007; 20(2): 117 - 122. [Abstract] [PDF]
|
|
|
|
 |
|
 N. Raghavachari, X. Xu, A. Harris, J. Villagra, C. Logun, J. Barb, M. A. Solomon, A. F. Suffredini, R. L. Danner, G. Kato, et al. Amplified Expression Profiling of Platelet Transcriptome Reveals Changes in Arginine Metabolic Pathways in Patients With Sickle Cell Disease Circulation, March 27, 2007; 115(12): 1551 - 1562. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Konishi, K. Sydow, and J. P. Cooke Dimethylarginine Dimethylaminohydrolase Promotes Endothelial Repair After Vascular Injury J. Am. Coll. Cardiol., March 13, 2007; 49(10): 1099 - 1105. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.-Y. Chong and G. Y.H. Lip Viewpoint: The prothrombotic state in heart failure: A maladaptive inflammatory response? Eur J Heart Fail, February 1, 2007; 9(2): 124 - 128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Shimasaki, Y. Saito, M. Yoshimura, S. Kamitani, Y. Miyamoto, I. Masuda, M. Nakayama, Y. Mizuno, H. Ogawa, H. Yasue, et al. The Effects of Long-term Smoking on Endothelial Nitric Oxide Synthase mRNA Expression in Human Platelets as Detected With Real-time Quantitative RT-PCR Clinical and Applied Thrombosis/Hemostasis, January 1, 2007; 13(1): 43 - 51. [Abstract] [PDF]
|
|
|
|
|
|
A. Schafer, U. Flierl, A. Kobsar, M. Eigenthaler, G. Ertl, and J. Bauersachs Soluble Guanylyl Cyclase Activation With HMR1766 Attenuates Platelet Activation in Diabetic Rats Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2813 - 2818. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. D. Zhao, D. W. Courtman, D. S. Ng, M. J. Robb, Y. P. Deng, J. Trogadis, R. N. N. Han, and D. J. Stewart Microvascular Regeneration in Established Pulmonary Hypertension by Angiogenic Gene Transfer Am. J. Respir. Cell Mol. Biol., August 1, 2006; 35(2): 182 - 189. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Heitzer, V. Rudolph, E. Schwedhelm, M. Karstens, K. Sydow, M. Ortak, P. Tschentscher, T. Meinertz, R. Boger, and S. Baldus Clopidogrel Improves Systemic Endothelial Nitric Oxide Bioavailability in Patients With Coronary Artery Disease: Evidence for Antioxidant and Antiinflammatory Effects Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1648 - 1652. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ekmekci and O. B. Ekmekci The Role of Adiponectin in Atherosclerosis and Thrombosis Clinical and Applied Thrombosis/Hemostasis, April 1, 2006; 12(2): 163 - 168. [Abstract] [PDF]
|
|
|
|
|
|
P. Kleinbongard, R. Schulz, T. Rassaf, T. Lauer, A. Dejam, T. Jax, I. Kumara, P. Gharini, S. Kabanova, B. Ozuyaman, et al. Red blood cells express a functional endothelial nitric oxide synthase Blood, April 1, 2006; 107(7): 2943 - 2951. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. V. Ovechkin, D. Lominadze, K. C. Sedoris, E. Gozal, T. W. Robinson, and A. M. Roberts Inhibition of inducible nitric oxide synthase attenuates platelet adhesion in subpleural arterioles caused by lung ischemia-reperfusion in rabbits J Appl Physiol, December 1, 2005; 99(6): 2423 - 2432. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Cella, M. Saetta, S. Baraldo, G. Turato, A. Papi, G. Casoni, and M. Rigno Endothelial Cell Activity in Chronic Obstructive Pulmonary Disease Without Severe Pulmonary Hypertension Clinical and Applied Thrombosis/Hemostasis, October 1, 2005; 11(4): 435 - 440. [Abstract] [PDF]
|
|
|
|
 |
|
 S. Verma and P. A. Marsden Nitric Oxide-Eluting Polyurethanes -- Vascular Grafts of the Future? N. Engl. J. Med., August 18, 2005; 353(7): 730 - 731. [Full Text] [PDF]
|
|
|
|
|
|
S. Rajagopalan, Q. Sun, and L. C. Chen Particulate Pollution and Endothelial Function: Deja Vu All Over Again in the Air Circulation, June 7, 2005; 111(22): 2869 - 2871. [Full Text] [PDF]
|
|
|
|
|
|
A. Schafer, D. Fraccarollo, M. Eigenthaler, P. Tas, A. Firnschild, S. Frantz, G. Ertl, and J. Bauersachs Rosuvastatin Reduces Platelet Activation in Heart Failure: Role of NO Bioavailability Arterioscler Thromb Vasc Biol, May 1, 2005; 25(5): 1071 - 1077. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Yamamoto, K. Takeshita, T. Kojima, J. Takamatsu, and H. Saito Aging and plasminogen activator inhibitor-1 (PAI-1) regulation: implication in the pathogenesis of thrombotic disorders in the elderly Cardiovasc Res, May 1, 2005; 66(2): 276 - 285. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. N. Morrell, K. Matsushita, K. Chiles, R. B. Scharpf, M. Yamakuchi, R. J. A. Mason, W. Bergmeier, J. L. Mankowski, W. M. Baldwin III, N. Faraday, et al. Regulation of platelet granule exocytosis by S-nitrosylation PNAS, March 8, 2005; 102(10): 3782 - 3787. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Krotz, H.-Y. Sohn, and U. Pohl Reactive Oxygen Species: Players in the Platelet Game Arterioscler Thromb Vasc Biol, November 1, 2004; 24(11): 1988 - 1996. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Cattaruzza, T. J. Guzik, W. Slodowski, A. Pelvan, J. Becker, M. Halle, A. B. Buchwald, K. M. Channon, and M. Hecker Shear Stress Insensitivity of Endothelial Nitric Oxide Synthase Expression as a Genetic Risk Factor for Coronary Heart Disease Circ. Res., October 15, 2004; 95(8): 841 - 847. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Fiorina, F. Folli, A. D'Angelo, G. Finzi, F. Pellegatta, V. Guzzi, C. Fedeli, P. D. Valle, L. Usellini, C. Placidi, et al. Normalization of Multiple Hemostatic Abnormalities in Uremic Type 1 Diabetic Patients After Kidney-Pancreas Transplantation Diabetes, September 1, 2004; 53(9): 2291 - 2300. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Schafer, N. J. Alp, S. Cai, C. A. Lygate, S. Neubauer, M. Eigenthaler, J. Bauersachs, and K. M. Channon Reduced Vascular NO Bioavailability in Diabetes Increases Platelet Activation In Vivo Arterioscler Thromb Vasc Biol, September 1, 2004; 24(9): 1720 - 1726. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Hongo, J. S. Bryson, A. M. Kaplan, and D. A. Cohen Endogenous Nitric Oxide Protects against T Cell-Dependent Lethality during Graft-versus-Host Disease and Idiopathic Pneumonia Syndrome J. Immunol., August 1, 2004; 173(3): 1744 - 1756. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Franscini, E. B. Bachli, N. Blau, M. Fischler, R. B. Walter, A. Schaffner, and G. Schoedon Functional Tetrahydrobiopterin Synthesis in Human Platelets Circulation, July 13, 2004; 110(2): 186 - 192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. P. Faxon, V. Fuster, P. Libby, J. A. Beckman, W. R. Hiatt, R. W. Thompson, J. N. Topper, B. H. Annex, J. H. Rundback, R. P. Fabunmi, et al. Atherosclerotic Vascular Disease Conference: Writing Group III: Pathophysiology Circulation, June 1, 2004; 109(21): 2617 - 2625. [Full Text] [PDF]
|
|
|
|
|
|
U. Landmesser, B. Hornig, and H. Drexler Endothelial Function: A Critical Determinant in Atherosclerosis? Circulation, June 1, 2004; 109(21_suppl_1): II-27 - II-33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rajagopalan, E. C. Somers, R. D. Brook, C. Kehrer, D. Pfenninger, E. Lewis, A. Chakrabarti, B. C. Richardson, E. Shelden, W. J. McCune, et al. Endothelial cell apoptosis in systemic lupus erythematosus: a common pathway for abnormal vascular function and thrombosis propensity Blood, May 15, 2004; 103(10): 3677 - 3683. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Napoli and J. Loscalzo Nitric Oxide and Other Novel Therapies for Pulmonary Hypertension Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2004; 9(1): 1 - 8. [Abstract] [PDF]
|
|
|
|
 |
|
 K. F. Harris and K. A. Matthews Interactions Between Autonomic Nervous System Activity and Endothelial Function: A Model for the Development of Cardiovascular Disease Psychosom Med, March 1, 2004; 66(2): 153 - 164. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. A. Massy, C. Fumeron, D. Borderie, P. Tuppin, T. Nguyen-Khoa, M.-O. Benoit, C. Jacquot, C. Buisson, T. B. Drueke, O. G. Ekindjian, et al. Increased Plasma S-Nitrosothiol Concentrations Predict Cardiovascular Outcomes among Patients with End-Stage Renal Disease: A Prospective Study J. Am. Soc. Nephrol., February 1, 2004; 15(2): 470 - 476. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. D. Wagner and P. C. Burger Platelets in Inflammation and Thrombosis Arterioscler Thromb Vasc Biol, December 1, 2003; 23(12): 2131 - 2137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Wang, L. Lin, J. Jiang, Y. Wang, Z. Y. Lu, J. A. Bradbury, F. B. Lih, D. W. Wang, and D. C. Zeldin Up-Regulation of Endothelial Nitric-Oxide Synthase by Endothelium-Derived Hyperpolarizing Factor Involves Mitogen-Activated Protein Kinase and Protein Kinase C Signaling Pathways J. Pharmacol. Exp. Ther., November 1, 2003; 307(2): 753 - 764. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Heitzer, I. Ollmann, K. Koke, T. Meinertz, and T. Munzel Platelet Glycoprotein IIb/IIIa Receptor Blockade Improves Vascular Nitric Oxide Bioavailability in Patients With Coronary Artery Disease Circulation, August 5, 2003; 108(5): 536 - 541. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Blann, S. Nadar, and G. Y.H. Lip Pharmacological Modulation of Platelet Function in Hypertension Hypertension, July 1, 2003; 42(1): 1 - 7. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. H. Shishehbor, R. J. Aviles, M.-L. Brennan, X. Fu, M. Goormastic, G. L. Pearce, N. Gokce, J. F. Keaney Jr, M. S. Penn, D. L. Sprecher, et al. Association of Nitrotyrosine Levels With Cardiovascular Disease and Modulation by Statin Therapy JAMA, April 2, 2003; 289(13): 1675 - 1680. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. A. Massy, D. Borderie, T. Nguyen-Khoa, T. B. Drueke, O. G. Ekindjian, and B. Lacour Increased plasma S-nitrosothiol levels in chronic haemodialysis patients Nephrol. Dial. Transplant., January 1, 2003; 18(1): 153 - 157. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Browne, D. Meeking, K. Shaw, and M. Cummings Review: Endothelial dysfunction and pre-symptomatic atherosclerosis in type 1 diabetes -- pathogenesis and identification The British Journal of Diabetes & Vascular Disease, January 1, 2003; 3(1): 27 - 34. [Abstract] [PDF]
|
|
|
|
 |
|
 U. Landmesser and H. Drexler Oxidative stress, the renin-angiotensin system, and atherosclerosis Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A3 - A7. [Abstract] [PDF]
|
|
|
|
|
|
S. Fiorucci, A. Mencarelli, A. Meneguzzi, A. Lechi, A. Morelli, P. del Soldato, and P. Minuz NCX-4016 (NO-Aspirin) Inhibits Lipopolysaccharide-Induced Tissue Factor Expression In Vivo: Role of Nitric Oxide Circulation, December 10, 2002; 106(24): 3120 - 3125. [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]
|
|
|
|
 |
|
 F. L Ruberg and J. Loscalzo Prothrombotic determinants of coronary atherothrombosis Vascular Medicine, November 1, 2002; 7(4): 289 - 299. [Abstract] [PDF]
|
|
|
|
|
|
L. Kalinowski, T. Matys, E. Chabielska, W. Buczko, and T. Malinski Angiotensin II AT1 Receptor Antagonists Inhibit Platelet Adhesion and Aggregation by Nitric Oxide Release Hypertension, October 1, 2002; 40(4): 521 - 527. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Rassaf, P. Kleinbongard, M. Preik, A. Dejam, P. Gharini, T. Lauer, J. Erckenbrecht, A. Duschin, R. Schulz, G. Heusch, et al. Plasma Nitrosothiols Contribute to the Systemic Vasodilator Effects of Intravenously Applied NO: Experimental and Clinical Study on the Fate of NO in Human Blood Circ. Res., September 20, 2002; 91(6): 470 - 477. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. J. Ignarro, C. Napoli, and J. Loscalzo Nitric Oxide Donors and Cardiovascular Agents Modulating the Bioactivity of Nitric Oxide: An Overview Circ. Res., January 11, 2002; 90(1): 21 - 28. [Abstract] [Full Text] [PDF]
|
|