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The Cyclic GMP Modulators YC-1 and Zaprinast Reduce Vessel Remodeling Through Antiproliferative and Proapoptotic Effects

Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas

Kelly J. Peyton, MA

Department of Medical Pharmacology & Physiology, University of Missouri, Columbia, Missouri

William Durante, PhD

Department of Medical Pharmacology & Physiology, University of Missouri, Columbia, Missouri

Andrew I. Schafer, MD

Weill Medical College of Cornell University, New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, New York

David A. Tulis, PhD

J.L. Chambers Biomedical/Biotechnology Research Institute and Department of Biology, North Carolina Central University, Durham, North Carolina, tulisd{at}ecu.edu, Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, North Carolina

Guanosine-specific cyclic nucleotide signaling is suggested to serve protective actions in the vasculature; however, the influence of selective pharmacologic modulation of cyclic guanosine monophosphate— synthesizing soluble guanylate cyclase or cyclic guanosine monophosphate—degrading phosphodiesterase on vessel remodeling has not been thoroughly examined. In this study, rat carotid artery balloon injury was performed and the growth-modulating effects of the soluble guanylate cyclase stimulator YC-1 or the cyclic guanosine monophosphate—dependent phosphodiesterase-V inhibitor zaprinast were examined. YC-1 or zaprinast elevated vessel cyclic guanosine monophosphate content, reduced medial wall and neointimal cell proliferation, stimulated medial and neointimal cellular apoptosis, and markedly attenuated neointimal remodeling in comparable fashion. Interestingly, soluble guanylate cyclase inhibition by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one failed to noticeably alter neointimal growth, and concomitant zaprinast with YC-1 did not modify any parameter compared to individual treatments. These results provide novel in vivo evidence that YC-1 and zaprinast inhibit injury-induced vascular remodeling through antimitogenic and proapoptotic actions and may offer promising therapeutic approaches against vasoproliferative disorders.

Key Words: apoptosis • carotid artery balloon injury • proliferation • YC-1 • zaprinast

This version was published on June 1, 2009

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 14, No. 2, 116-124 (2009)
DOI: 10.1177/1074248409333266


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