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217 c reactive protein


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217 c reactive protein

  1. 1. C-Reactive Protein is a Vasoreactive Substance?! Provided by: Subodh Verma, M.D., Ph.D. Division of Cardiac Surgery University of Toronto, Toronto, ON, Canada Editorial Slides VP Watch – October 9, 2002 - Volume 2, Issue 40
  2. 2.  Inflammation is now considered to be at the root of atherosclerosis.1,2  Markers of inflammation, such as C-Reactive Protein (CRP), have been demonstrated to be associated with the development of atherosclerosis and cardiovascular disease.3,4 Inflammation and Atherosclerosis
  3. 3.  CRP has been shown to predict the development of future cardiovascular disease.5,6  Recently CRP has been found to be localized in atherosclerotic plaques and induces the expression of proatherogenic cell adhesion molecules, cytokines such as MCP-1 and IL-6, and vasoreactive substances such as ET-1.7,8  CRP also has been found to decrease endothelial NO synthesis which results in endothelial dysfunction.9 C-Reactive Protein and Atherosclerosis
  4. 4.  Elevated CRP is associated with blunted systemic endothelial vasodilator function in addition to endothelial dysfunction present in acute coronary syndromes.10,11  Fichtlscherer et al. were able to demonstrate an inverse relationship between endothelium- dependent blood flow responses and CRP serum levels in patients with CAD.10 CRP and Vasoreactivity
  5. 5.  Fichtlscherer et al. measured endothelium-dependent forearm blood flow responses with venous plethysmography in patients with angiographically documented CAD. Endothelium- dependent forearem blood flow responses were inversely correlated to CRP serum leves.10 CRP and Endothelium-Dependent Vasoreactivity
  6. 6.  Cleland et al. investigated the relationship between chronic low grade inflammation (indicated by CRP levels) and endothelial NO synthesis as an indicator of endothelial function.12  Their results indicated, for the first time, that elevated CRP is associated with decreased endothelial NO synthesis as indicated by blood flow responses to L-NMMA. 12 Endothelial dysfunction and CRP
  7. 7. • These two studies both clearly demonstrate that CRP is associated with endothelial dysfunction and but do not tell us anything about any potential s direct effect CRP has on vasoreactivity…
  8. 8.  As reported in VP Watch of this week, Sternik et al. show for the first time the potent direct vasodilatory effect of CRP on human internal mammary artery segments.13 Organ bath experiments were utilized to assess the vasoreactive effect of varying concentrations of CRP on precontracted (with ET-1) IMA segments.13
  9. 9.  They showed that CRP was able to vasodilate human IMA in a dose-dependent manner and that this response was not attenuated by the removal of the endothelium.  Further experiments demonstrated that this vasorelaxatory response to CRP is NO independent, since incubation with L-NMMA, an inhibitor of NO synthase, did not attenute this vasodilatory response. Results
  10. 10. Vasorelaxation Response of IMAs to CRP Leonid Sternik, Saquib Samee, Hartzel V. Schaff, Kenton J. Zehr, Lilach O. Lerman, David R. Holmes, Joerg Herrmann, Amir Lerman; C-Reactive Protein Relaxes Human Vessels In Vitro Arteriocler Thromb Vasc Biol. 2002 22: ??? - ??? 0 10 20 30 40 50 60 70 80 90 100 -10.5 -10 -9.5 -9 -8.5 -8 -7.5 -7 -6.5 -6 CRP [log mol/L] %Relaxation IMA IMA E-
  11. 11.  Since hyperpolarization of VSMCs in response to activation of potassium channels has been identifed as an important mechanism of vasodilation, Sternik et al. investigated the role of K+ channels in CRP inducted vasodilation.  Their results obtained using preincubation with varying concentration of KCl as well as the K+ channel inhibitors, BaCl and TEA indicate the Potassium Channels are mediators of CRP’s vasorelaxing effect on IMA segments. Results
  12. 12. Conclusion:  C-Reactive Protein has a direct endothelium-independent vasodilatory effect.  This response is mediated, at least in part, through potassium channels on vascular smooth muscle cells.
  13. 13. Conclusion:  This study provides important evidence supporting the theory that CRP is more than just a marker of inflammation and is likely a key direct participant in the chronic inflammatory process associated with atherosclerosis.
  14. 14. Questions: • Does CRP act directly on VSMCs or is their an intermediate signalling molecule such as ET-1 involved in autocrine/paracrine signalling? • Are there pharmacologic agents such as ET-1 receptor antagonists (Bosentan) that blunt CRP’s effect on vasorelaxation?
  15. 15. Questions: • Does CRP induced vasorelaxation play a role in development of long-term atherosclerosis and plaque formation? • Is CRP more of a trigger that causes plaque instability or vulnerable plaque resulting in rupture and thrombosis?
  16. 16. 1) Libby P, Ridker PM, Maseri A. Inflammation and Atherosclerosis. Circulation 2002;105:1135-1143. 2) Libby P. Atherosclerosis: The New View. Sci Am 2002;286:46-55. 3) Saadeddin SM, Habbab MA, Ferns GA. Markers of Inflammation and Coronary Artery Disease. Med Sci Monit 2002;8:RA5-12. 4) Rader DJ. Inflammatory Markers of Coronary Risk. N Engl J Med 2000;343:1179-1182. 5) Rifai N, Ridker PM. High-Sensitivity C-Reactive Protein: A Novel and Promising Marker of Coronary Heart Disease. Clin Chem 2001;47:403-411. 6) Kushner I. C-Reactive Protein and Atherosclerosis. Science 2002;297:520-521. 7) Pasceri V, Willerson JT, Yeh ET. Direct Proinflammatory Effect of C-Reactive Protein on Human Endothelial Cells. Circulation 2000;102:2165-2168. 8) Verma S, Li SH, Badiwala MV, Weisel RD, Fedak PWM, Li RK, Dhillon B, Mickle DA. Endothelin Antagonism and Interleukin-6 Inhibition Attenuate the Proatherogenic Effects of C-Reactive Protein. Circulation 2002;105:1890-1896. 9) Verma S, Wang CH, Li SH, Dumont AS, Fedak PWM, Badiwala MV, Dhillon B, Weisel RD, Li RK, Mickle DAG, Stewart DJ. A Self-Fulfilling Prophecy: C-Reactive Protein Attenuates Nitric Oxide Production and Inhibits Angiogenesis. Circulation 2002;106:913-919. 10) Fichtlscherer S, Rosenberger G, Walter DH, Breuer S, Dimmeler S, Zeiher AM. Elevated C-Reactive Protein Levels and Impaired Endothelial Vasoreactivity in Patients with Coronary Artery Disease. Circulation 2000;102:1000-1006. 11) Fichtlscherer S, Zeiher AM. Endothelial Dysfunction in Acute Coronary Syndromes: Association with Elevated C-Reactive Protein Levels. Ann Med 2000;32:515-518. 12) Cleland SJ, Sattar N, Petrie JR, Forouhi NG, Elliott HL, Connell JMC. Endothelial Dysfunction as a Possible Link Between C-Reactive Protein Levels and Cardiovascular Disease. Clinical Science 2000;98:531-535. References