Age-related decrease in 15-lipoxygenase contributes to reduced vasorelaxation in rabbit aorta.
Rabbit 15-lipoxygenase-1 (15-LO-1) oxygenates arachidonic acid (AA) into 15-hydroperoxyeicosatetraenoic acid, which is then converted to the vasodilatory 15-hydroxy-11,12-epoxyeicosatrienoic acid (HEETA) and 11,12,15-trihydroxyeicosatrienoic acid (THETA). We studied the age-dependent expression of the 15-LO-1 in rabbit aorta and its effects on the synthesis of THETA, HEETA, and vasoactivity. Aortas of 1-wk-old rabbits express greater amounts of 15-LO-1 mRNA and protein compared with aortas of 4-, 8-, or 16-wk-old rabbits. The synthesis of THETA and HEETA in the rabbit aorta was also reduced with age. THETA synthesis was maximal in 1-wk-old aortas but decreased in aortas of 4- (42%), 8- (4%), and 16-wk-old (1%) rabbits. Similarly, THETA and HEETA synthesis decreased with age in mesenteric arteries from 1-, 4-, 8-, and 16-wk-old rabbits. The maximum vasorelaxation response to acetylcholine (10(-6) M) in the presence of indomethacin and nitro-l-arginine decreased in the order of 1 wk (64.5 +/- 6.9%), 4 wk (52.6 +/- 8.9%), 8 wk (53.0 +/- 9.4%), and 16 wk (33.3 +/- 6.6%). Similarly, the maximum relaxation to AA (3 x 10(-4) M) decreased with age in the order of 1 wk (60.4 +/- 8.9%), 4 wk (56.3 +/- 5.8%), 8 wk (41.8 +/- 12.3%), and 16 wk (28.9 +/- 1.6%). In contrast, the vasorelaxation to sodium nitroprusside was not significantly altered by age. These data indicate that aortic 15-LO-1 expression and activity are downregulated with aging in rabbits. This decrease is paralleled by the reduced synthesis of vasoactive THETA and HEETA and aortic relaxations to acetylcholine and AA.
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Xin
X
Tang
Nitin
N
Aggarwal
Blythe B
BB
Holmes
Hartmut
H
Kuhn
William B
WB
Campbell
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000109:Acetylcholine / Q000494:pharmacology; D000375:Aging / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001011:Aorta / Q000201:enzymology / Q000254:growth & development / Q000502:physiology; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism / Q000494:pharmacology; D001685:Biological Factors / Q000378:metabolism; D015153:Blotting, Western; D003001:Cloning, Molecular; D066298:In Vitro Techniques; D007700:Kinetics; D008969:Molecular Sequence Data; D009126:Muscle Relaxation / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000254:growth & development* / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014665:Vasodilator Agents / Q000494:pharmacology
D001685:Biological Factors; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; C080015:11-hydroxy-8,9-epoxyeicosatrienoic acid; D009599:Nitroprusside; D016718:Arachidonic Acid; D012313:RNA; C066049:11,12,15-trihydroxyeicosatrienoic acid; D001093:Arachidonate 15-Lipoxygenase; D015126:8,11,14-Eicosatrienoic Acid; D000109:Acetylcholine