Faculty Collaboration Database

Hypercholesterolemia enhances 15-lipoxygenase-mediated vasorelaxation and acetylcholine-induced hypotension. Arterioscler Thromb Vasc Biol 2008 Dec;28(12):2209-15

Date

10/04/2008

Pubmed ID

18832753

DOI

10.1161/ATVBAHA.108.177113

Scopus ID

2-s2.0-57549097264 (requires institutional sign-in at Scopus site)   12 Citations

Abstract

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 (14)C-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%.

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

Author List

Aggarwal NT, Pfister SL, Campbell WB

Authors

William B. Campbell PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Sandra L. Pfister PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

8,11,14-Eicosatrienoic Acid
Acetylcholine
Animals
Aorta
Arachidonate 15-Lipoxygenase
Arachidonic Acid
Arteries
Blood Pressure
Hypercholesterolemia
Hypotension
In Vitro Techniques
Lipoxygenase Inhibitors
Male
RNA, Messenger
Rabbits
Vasodilation