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J Thorac Cardiovasc Surg 2007;133:1137-1146
© 2007 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Endothelin-1 accentuates the proatherosclerotic effects associated with C-reactive protein

Danny Ramzy, MDb, Vivek Rao, MD, PhDb,*, Laura C. Tumiati, BScb, Ning Xu, MD, MScb, Rohit Sheshgiri, BSca, Jessica Jackman, BSca, Diego H. Delgado, MDc, Heather J. Ross, MD, MScc

a Heart Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
b Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada
c Division of Cardiology, University of Toronto, Toronto, Ontario, Canada.

Read at the Eighty-sixth Annual Meeting of The American Association for Thoracic Surgery, Philadelphia, Pa, April 29-May 3, 2006.

Received for publication April 28, 2006; revisions received October 18, 2006; accepted for publication November 1, 2006.

* Address for reprints: Vivek Rao, MD, PhD, FRCS, Alfredo and Teresa DeGasperis Chair in Heart Failure Surgery, 4N-464, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario, M5G 2C4, Canada (Email: vivek.rao{at}uhn.on.ca).

Objectives: The proinflammatory marker C-reactive protein has been demonstrated to play a role in the development of atherosclerosis. Endothelin-1 and nitric oxide homeostasis is crucial for normal vasomotor function, limiting inflammatory activation and maintaining a nonthrombogenic endothelial surface. In addition to its vasoactive properties, endothelin-1 is also an inflammatory cytokine. We have previously demonstrated that C-reactive protein impairs endothelial cell nitric oxide production. Protein kinase C, an important signal transducer within the cell, is involved in several cellular responses to external stimuli. We therefore sought to determine whether endothelin-1 exposure modulates C-reactive protein’s effects on nitric oxide production via protein kinase C.

Methods: Endothelial cells were incubated with C-reactive protein (200 µg), endothelin-1 (100 nM), C-reactive protein + endothelin-1, or phosphate-buffered saline solution (control) for 24 hours. After exposure, endothelial nitric oxide synthase expression was determined in addition to total nitric oxide production and protein kinase C translocation and activity.

Results: Endothelial nitric oxide synthase protein expression was reduced following incubation with C-reactive protein and endothelin-1 treatment compared with baseline by 40% and 45%, respectively (P = .04); however, no additive effects were seen with coincubation. C-reactive protein produced a 47% decrease in nitric oxide production compared with control. Coincubation with endothelin-1 resulted in a synergistic 70% reduction in nitric oxide production (P = .001). C-reactive protein exposure inhibited translocation of protein kinase C{lambda} compared with control (P = .01). Furthermore, coincubation of C-reactive protein with endothelin-1 led to a synergistic inhibition of protein kinase C{lambda} translocation (P = .01). C-reactive protein exposure reduced protein kinase C activity by 40% compared with control (P = .02), although coincubation with endothelin-1 had a synergistic reduction in activity (P = .02).

Conclusions: Our results indicate that endothelin-1 exposure accentuated C-reactive protein’s impairment of endothelial nitric oxide production via synergistic inhibition of protein kinase C{lambda} translocation and activity. Our investigations suggest that endothelin-1 inhibition and protein kinase C stimulation may provide a novel therapeutic strategy to improve vascular nitric oxide homeostasis and mitigate the proatherosclerotic effects of C-reactive protein.

Abbreviations and Acronyms CRP = C-reactive protein; eNOS = endothelial nitric oxide synthase; ET-1 = endothelin-1; HSVEC = human saphenous vein endothelial cell; M/C = membrane-to-cytosolic (ratio); NO = nitric oxide; PKC = protein kinase C; PMA = phorbol 12-myristate 13-acetate


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Discussion
J. Thorac. Cardiovasc. Surg. 2007 133: 1145-1146. [Extract] [Full Text] [PDF]





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