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Cardiovascular Research 2004 64(2):192-194; doi:10.1016/j.cardiores.2004.07.008
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

Direct vasoprotection by aspirin: a significant bonus to antiplatelet activity?

Georg Kojda*

Institut für Pharmakologie und Klinische Pharmakologie, Medizinische Einrichtungen, Heinrich-Heine-Universität, Moorenstr. 5, 40225 Düsseldorf, Germany

* Tel.: +49 211 81 12518; fax: +49 211 81 14781. Email address: kojda{at}uni-duesseldorf.de

Received 13 July 2004; accepted 15 July 2004

See article by Mehta et al. [14] (pages 243–249) in this issue.


   1. Introduction
Top
 1. Introduction
2. Antiplatelet activity
 3. Vascular effects
 4. Vascular molecular mechanisms
 References
 
Acetylsalicylic acid (aspirin) is an important drug in cardiovascular medicine. The evaluation in large clinical trials of its efficacy in preventing acute coronary events began about 20 years ago [1,2] and is still ongoing. An important consequence of this is the worldwide recommendation to use low-dose aspirin for primary and secondary prevention of myocardial infarction and for treatment of unstable angina and non-ST-segment myocardial infarction [3,4]. Likewise, aspirin can be used safely for the prevention of vascular events in the cerebral and peripheral circulation, although higher doses might be required than for prevention of acute coronary events [5]. The knowledge about beneficial effects of aspirin has been rapidly and effectively translated into clinical practice. The results of the EUROASPIRE II Euro Heart Survey Program demonstrated that 86% of coronary patients received aspirin 6 months after discharge from the hospital, while the frequency of prescription of other recommended drugs such as β-blockers (63%), ACE-inhibitors (38%) and lipid-lowering drugs (61%) was considerably lower [6].


   2. Antiplatelet activity
Top
 1. Introduction
 2. Antiplatelet activity
3. Vascular effects
 4. Vascular molecular mechanisms
 References
 
The beneficial effects of aspirin are directly related to its antiplatelet effects induced by selective inhibition of platelet cyclooxygenase 1 (COX-1) [5]. This selectivity is largely mediated by the unique and irreversible acetylation of Ser530 in human COX-1, a region near the carboxyl terminus of the COX-1 protein that is in close proximity to the catalytic binding site for arachidonic acid (Tyr385 in the active center) [7]. Acetylation inhibits binding of arachidonic acid and, hence, generation of prostaglandin H2, an intermediate of platelet thromboxane formation. This mechanism of irreversible COX-1 inhibition provides a sufficient explanation for selective inhibition of COX-1 by low-dose aspirin in platelets that–in striking contrast to vascular cells–cannot replace acetylated COX-1 by de novo COX-1 synthesis. Therefore, it is not surprising that drugs which inhibit COX in a competitive manner show a plasma concentration-dependent inhibition of platelet aggregation but have no clinically useful antiplatelet effects [5]. In fact, ibuprofen can inhibit the antiplatelet activity of aspirin [8]. The most likely explanation for this interaction is that ibuprofen bound to COX-1 of platelets inhibits the access of aspirin to the catalytic pocket and thus acetylation of Ser530.


   3. Vascular effects
Top
 1. Introduction
 2. Antiplatelet activity
 3. Vascular effects
4. Vascular molecular mechanisms
 References
 
The broad clinical use of aspirin is still stimulating many researchers to further evaluate the molecular mechanisms underlying the reduction of cardiovascular events by this drug. It is well accepted that cardiovascular diseases such as atherosclerosis, coronary artery disease, heart failure, hypertension and diabetes are associated with increased vascular oxidative stress, and a similar association has been shown for the cardiovascular risk factors smoking, hyperglycemia and hypercholesterolemia [9]. Thus, many studies attempted to investigate the effect of aspirin on vascular oxidative stress. A study in smokers revealed no effect of aspirin on the isoprostane 8-epi-PGF2{alpha}, a urinary marker of oxidative stress [10]. In contrast, it was shown that aspirin protects cultured endothelial cells from oxidative stress, suggesting a direct vasoprotective effect [11]. Likewise, aspirin reversed the impairment of endothelium-dependent forearm vasodilation to acetylcholine in normotensive, non-obese hypercholesterolemic human subjects [12]. Vascular antioxidative properties of aspirin were also noted in a study with spontaneously hypertensive rats [13].


   4. Vascular molecular mechanisms
Top
 1. Introduction
 2. Antiplatelet activity
 3. Vascular effects
 4. Vascular molecular mechanisms
References
 
In this issue of the Journal, Metha et al. [14] report on a new mechanism by which aspirin may reduce vascular oxidative stress. In this study, the authors demonstrate the ability of aspirin to inhibit in a concentration dependent manner the expression of the lectin-like receptor LOX-1 that was induced by oxidized low density lipoprotein (oxLDL) in endothelial cells. In a further series of experiments, they go on to show that this inhibition is associated with an inhibition of the expression of matrix metalloproteinase-1 (MMP-1), which was also stimulated by ox-LDL. At the same time, phosphorylation of p38 MAPK and endothelial generation of superoxide disappear. These data suggest that aspirin may protect endothelial cells from detrimental effects of oxLDL such as increased generation of superoxide and stimulation of LOX-1 and MMP-1 expression.

A closer look to the results of Mehta et al. reveals some interesting details. Salicylate also reduced the induction of LOX-1 expression by oxLDL, suggesting that the unique capability of aspirin to acetylate proteins is not the underlying mechanism. It should be noted that the concentrations needed for these effects of aspirin and salicylate exceed the plasma concentrations found after low-dose aspirin therapy in humans, which are 2.9–33.3 µM for aspirin and 18.1–245 µM for salicylate after up to 460 mg aspirin [15]. The effects of salicylate on gene expression have been linked to mechanisms that appear to depend on the salicylate steady-state concentration. While salicylate concentrations reflecting low-dose aspirin inhibit binding of the transcription factor CCAAT/enhancer binding protein (C/EBPβ) and subsequent initiation of transcription [16], salicylate concentrations reflecting high-dose aspirin may additionally inhibit the activity of I{kappa}B kinase β (Ikkβ) and subsequently the phosphorylation I{kappa}B and activation of NF{kappa}B [17].

Another important question is whether the inhibitory effects of aspirin on oxLDL-induced LOX-1 and MMP-1 expression involve changes in endothelial NO bioavailability. It was shown that oxLDL potently reduces endothelial NO bioavailability by inhibition of cellular uptake of L-arginine, the substrate of endothelial NO-synthase [18], and/or by direct induction of endothelial NADPH oxidase [19]. There is compelling evidence demonstrating that a reduction of endothelial NO bioavailability increases vascular oxidative stress and promotes the atherosclerotic process [20]. Recently, aspirin has been shown to protect endothelial cells from hydrogen peroxide toxicity in an NO-dependent manner [21].

Finally, further studies are needed to demonstrate that inhibition of LOX-1 and MMP-1 expression by aspirin occurs in vivo. Previous studies have yielded conflicting results on vascular effects of aspirin in hypercholesterolemia. While aspirin reduced the development of atherosclerosis in hypercholesterolemic rabbits [22] and LDL receptor-deficient mice [23], it had no effect on atherogenesis in hypercholesterolemic miniature pigs [24] and LDL receptor-deficient mice [25].

In summary, some evidence suggests that a direct vascular activity of both aspirin and salicylate is involved in the beneficial effects of aspirin in coronary artery disease. These effects may include changes in the expression of LOX-1 and MMP-1. What is needed now are in vivo studies to substantiate the current experimental evidence.


   Acknowledgements
 
I wish to thank Prof. Dr. Karsten Schrör (director of the institute) for his critical comments.


   References
Top
 1. Introduction
 2. Antiplatelet activity
 3. Vascular effects
 4. Vascular molecular mechanisms
 References
 

  1. Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. Steering Committee of the Physicians' Health Study Research Group. N. Engl. J. Med. (1989) 321:129–135.[Abstract]
  2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet (1988) 2(8607):349–360.[Medline]
  3. Anonymous. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ (2002) 324:71–86.[Abstract/Free Full Text]
  4. Braunwald E. Application of current guidelines to the management of unstable angina and non-ST-elevation myocardial infarction. Circulation (2003) 108:III28–III37.[Medline]
  5. Schror K. Aspirin and platelets: the antiplatelet action of aspirin and its role in thrombosis treatment and prophylaxis. Semin. Thromb. Hemost. (1997) 23:349–356.[Medline]
  6. EUROASPIRE II Study Group. Lifestyle and risk factor management and use of drug therapies in coronary patients from 15 countries; principal results from EUROASPIRE II Euro Heart Survey Programme. Eur. Heart J. (2001) 22:554–572.[Abstract/Free Full Text]
  7. DeWitt D.L., Smith W.L. Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from the complementary DNA sequence. Proc. Natl. Acad. Sci. U. S. A. (1988) 85:1412–1416.[Abstract/Free Full Text]
  8. Catella-Lawson F., Reilly M.P., Kapoor S.C., et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N. Engl. J. Med. (2001) 345:1809–1817.[Abstract/Free Full Text]
  9. Kojda G., Harrison D.G. Interactions between NO and reactive oxygen species: pathophysiological importance in atherosclerosis, hypertension, diabetes and heart failure. Cardiovasc. Res. (1999) 43:562–571.[CrossRef][Web of Science][Medline]
  10. Reilly M., Delanty N., Lawson J.A., FitzGerald G.A. Modulation of oxidant stress in vivo in chronic cigarette smokers. Circulation (1996) 94:19–25.[Abstract/Free Full Text]
  11. Oberle S., Polte T., Abate A., Podhaisky H.P., Schroder H. Aspirin increases ferritin synthesis in endothelial cells: a novel antioxidant pathway. Circ. Res. (1998) 82:1016–1020.[Abstract/Free Full Text]
  12. Noon J.P., Walker B.R., Hand M.F., Webb D.J. Impairment of forearm vasodilatation to acetylcholine in hypercholesterolemia is reversed by aspirin. Cardiovasc. Res. (1998) 38:480–484.[Abstract/Free Full Text]
  13. Wu R., Lamontagne D., de Champlain J. Antioxidative properties of acetylsalicylic acid on vascular tissues from normotensive and spontaneously hypertensive rats. Circulation (2002) 105:387–392.[Abstract/Free Full Text]
  14. Mehta J.L., Chen J., Yu F., Li D.Y. Aspirin inhibits ox-LDL-mediated LOX-1 expression and metalloproteinase-1 in human coronary endothelial cells. Cardiovasc. Res. (2004) 64:243–249.[Abstract/Free Full Text]
  15. Dahlen B., Boreus L.O., Anderson P., Andersson R., Zetterstrom O. Plasma acetylsalicylic acid and salicylic acid levels during aspirin provocation in aspirin-sensitive subjects. Allergy (1994) 49:43–49.[Web of Science][Medline]
  16. Saunders M.A., Sansores-Garcia L., Gilroy D.W., Wu K.K. Selective suppression of CCAAT/enhancer-binding protein beta binding and cyclooxygenase-2 promoter activity by sodium salicylate in quiescent human fibroblasts. J. Biol. Chem. (2001) 276:18897–18904.[Abstract/Free Full Text]
  17. Yuan M., Konstantopoulos N., Lee J., et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science (2001) 293:1673–1677.[Abstract/Free Full Text]
  18. Vergnani L., Hatrik S., Ricci F., et al. Effect of native and oxidized low-density lipoprotein on endothelial nitric oxide and superoxide production: key role of L-arginine availability. Circulation (2000) 101:1261–1266.[Abstract/Free Full Text]
  19. Rueckschloss U., Galle J., Holtz J., Zerkowski H.R., Morawietz H. Induction of NAD(P)H oxidase by oxidized low-density lipoprotein in human endothelial cells: antioxidative potential of hydroxymethylglutaryl coenzyme A reductase inhibitor therapy. Circulation (2001) 104:1767–1772.[Abstract/Free Full Text]
  20. Gewaltig M.T., Kojda G. Vasoprotection by nitric oxide: mechanisms and therapeutic potential. Cardiovasc. Res. (2002) 55:250–260.[Abstract/Free Full Text]
  21. Grosser N., Schroder H. Aspirin protects endothelial cells from oxidant damage via the nitric oxide-cGMP pathway. Arterioscler. Thromb. Vasc. Biol. (2003) 23:1345–1351.[Abstract/Free Full Text]
  22. Prasad K., Lee P. Suppression of oxidative stress as a mechanism of reduction of hypercholesterolemic atherosclerosis by aspirin. J. Cardiovas. Pharmacol. Ther. (2003) 8:61–69.[CrossRef]
  23. Cyrus T., Sung S., Zhao L., Funk C.D., Tang S., Pratico D. Effect of low-dose aspirin on vascular inflammation, plaque stability, and atherogenesis in low-density lipoprotein receptor-deficient mice. Circulation (2002) 106:1282–1287.[Abstract/Free Full Text]
  24. Smith M.J., Allen K.G., Norman J.F., Harris M.A., Miller C.W. Low-dose aspirin does not attenuate platelet aggregation or atherosclerosis in miniature swine but decreases production of aortic wall prostacyclin. Prostaglandins, Leukot. Essent. Fat. Acids (1995) 53:331–340.[CrossRef]
  25. Napoli C., Cirino G., Del Soldato P., et al. Effects of nitric oxide-releasing aspirin versus aspirin on restenosis in hypercholesterolemic mice. Proc. Natl. Acad. Sci. U. S. A. (2001) 98:2860–2864.[Abstract/Free Full Text]

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This Article
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