This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 28/12/2209    most recent ATVBAHA.108.177113v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Aggarwal, N. T. Articles by Campbell, W. B. Search for Related Content PubMed PubMed Citation Articles by Aggarwal, N. T. Articles by Campbell, W. B.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2209.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Hypercholesterolemia Enhances 15-Lipoxygenase–Mediated Vasorelaxation and Acetylcholine-Induced Hypotension

Nitin T. Aggarwal; Sandra L. Pfister; William B. Campbell

From the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee.

Correspondence to William B. Campbell, PhD, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. E-mail wbcamp{at}mcw.edu

Objective— Arachidonic acid (AA) metabolites from 15-lipoxygenase-1 (15-LO-1), trihydroxyeicosatrienoic acid (THETA), and hydroxyepoxyeicosatrienoic acid (HEETA) relax arteries. We studied 15-LO-1 expression, THETA and HEETA synthesis, and their effect on arterial relaxations and blood pressure in hypercholesterolemic nonatherosclerotic rabbits.

Methods and Results— Immunoblots, RTPCR analysis, and ¹⁴C-AA metabolism revealed that hypercholesterolemia increased 15-LO-1 expression in the endothelium and THETA and HEETA synthesis in the arteries. Isometric tension recording, in presence of nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibitors, showed greater relaxations to acetylcholine (ACH) and AA (max 76.0±4.6% and 79.5±2.4%, respectively) in aortas from hypercholesterolemic rabbits compared with normal rabbits (max 39.1±2.8% and 39.9±2.2%, respectively). AA induced greater hyperpolarization in the smooth muscle cells of hypercholesterolemic aortas (–45.85±3.0 mV) compared with normal aortas (–31.45±1.9 mV). The ACH- and AA-relaxations were inhibited by 15-LO-1 inhibitors. ACH induced hypotensive responses were greater in hypercholesterolemic rabbits in absence (–54.9±3.3%) or presence (–48.5±3.2%) of NOS and COX-inhibitors compared with control rabbits (–31.6±3.3% and –24.3±1.6%, respectively). BW755C reduced these responses in hypercholesterolemic rabbits to –29.3±2.3%.

Conclusion— Hypercholesterolemia increases endothelial 15-LO-1 expression, THETA and HEETA synthesis and enhances vasorelaxation.

Key Words: hypercholesterolemia • 15-lipoxygenase • endothelium-derived hyperpolarizing factors • blood pressure • arachidonic acid

This article has been cited by other articles:

				Y. Chawengsub, K. M. Gauthier, K. Nithipatikom, B. D. Hammock, J. R. Falck, D. Narsimhaswamy, and W. B. Campbell Identification of 13-Hydroxy-14,15-epoxyeicosatrienoic Acid as an Acid-stable Endothelium-derived Hyperpolarizing Factor in Rabbit Arteries J. Biol. Chem., November 6, 2009; 284(45): 31280 - 31290. [Abstract] [Full Text] [PDF]

				Y. Chawengsub, K. M. Gauthier, and W. B. Campbell Role of arachidonic acid lipoxygenase metabolites in the regulation of vascular tone Am J Physiol Heart Circ Physiol, August 1, 2009; 297(2): H495 - H507. [Abstract] [Full Text] [PDF]