C-reactive protein impairs coronary microvascular function : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
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College Station, Tex. :
Texas A&M University System Health Science Center,
2007.
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| Subjects: |
| Abstract: | ABSTRACT: Elevated levels of C-reactive protein (CRP), a pro-inflammatory marker, are associated with reduced systemic endothelium-dependent nitric oxide (NO)-mediated dilation in patients with coronary artery disease; however, the direct effect of CRP on coronary microvascular reacticity remains unknown. Herein, we examined whether CRP can modulate endothelium-dependent vasodilatory pathways, and whether pro-inflammatory signaling pathways such as stress-activated protein kinases (p38 and JNK) and oxidative stress are involved in the CRP-mediated effect. Porcine coronary arterioles were isolated and pressurized without flow for in vitro study. Intraluminal treatment with a clinically relevant concentration of CRP (7 ug/mL, 1 hour) significantly attenuated the NO release and vasodilation to serotonin. Further incubation with the NO precursor L-arginine partially restored serotonin-induced vasodilation. The detrimental effect of CRP on serotonin-induced dilation was prevented in the presence of the superoxide scavenger TEMPOL, the NAD(P)H oxidase inhibitor apocynin, or the p38 kinase (an upstream activator of NAD(P)H oxidase) inhibitor SB203850, but not the xanthine oxidase inhibitor allopurinol or the c-Jun N-terminal kinase inhibitor SP600125. Dihydroethidium staining showed that CRP produced SB203850- and TEMPOL-sensitive superoxide production in the arteriolar endothelium. CRP treatment of coronary arterioles significantly increased NAD(P)H oxidase activity. Intraluminal treatment with CRP also attenuated endothelium-dependent, protacyclin (PGI₂)-mediated dilation to arachidonic acid (AA) and inhibited PGI₂ release from coronary microvessels. However, CRP did not affect endothelium-derived hyperpolarizing factor (EDHF)-mediated dilation to bradykinin. Scavenging peroxynitrite (a byproduct of superoxide and NO) with urate prevented the effect of CRP on the PGI₂-mediated dilation and PGI₂ release. LOX-1 receptor blockade with its antagonist k-carrageenan and LOX-1 antibody prevented the CRP effects on NO- and PGI₂-mediated pathways. The presence of LOX-1 receptor in porcine coronary arterioles was verified by immunohistochemical staining. In conclusion, by stimulating the LOX-1 receptor, and subsequent activation of NAD(P)H oxidase through p38 kinase, CRP inhibits endothelium-dependent NO- and PGI₂-mediated dilation in coronary arterioles through increased superoxide and peroxynitrite production, respectively. By impairing endothelium-dependent vasoreactivity, CRP can potentially facilitate the initiation of numerous cardiovascular diseases. |
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| Item Description: | Vita. "Major Subject: Medical Sciences". "Submitted to the Graduate School of Biomedical Sciences of The Texas A&M University System Health Science Center in partial fulfillment for the requirements for the degree of Doctor of Philosophy May 2007." Approved as to style and content by: Lih Kuo, Michael Davis, Travis Hein, Emily Wilson, Harris Granger. |
| Physical Description: | viii, 99 leaves : illustrations ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 83-98). |