Effect of Human 15-lipoxygenase-1 Metabolites on Vascular Function in Mouse Mesenteric Arteries and Hearts

Overview

Journal Prostaglandins Other Lipid Mediat

Date 2013 Jul 23

PMID 23872364

Citations 5

Authors

Tamas Kriska

Cody Cepura

Lawan Siangjong

Tina C Wan

John A Auchampach

Aviv Shaish

Dror Haratz

Ganesh Kumar

John R Falck

Kathryn M Gauthier

William B Campbell

Affiliations

Soon will be listed here.

Abstract

Lipoxygenases regulate vascular function by metabolizing arachidonic acid (AA) to dilator eicosanoids. Previously, we showed that endothelium-targeted adenoviral vector-mediated gene transfer of the human 15-lipoxygenase-1 (h15-LO-1) enhances arterial relaxation through the production of vasodilatory hydroxyepoxyeicosatrienoic acid (HEETA) and trihydroxyeicosatrienoic acid (THETA) metabolites. To further define this function, a transgenic (Tg) mouse line that overexpresses h15-LO-1 was studied. Western blot, immunohistochemistry and RT-PCR results confirmed expression of 15-LO-1 transgene in tissues, especially high quantity in coronary arterial wall, of Tg mice. Reverse-phase HPLC analysis of [(14)C]-AA metabolites in heart tissues revealed enhanced 15-HETE synthesis in Tg vs. WT mice. Among the 15-LO-1 metabolites, 15-HETE, erythro-13-H-14,15-EETA, and 11(R),12(S),15(S)-THETA relaxed the mouse mesenteric arteries to the greatest extent. The presence of h15-LO-1 increased acetylcholine- and AA-mediated relaxation in mesenteric arteries of Tg mice compared to WT mice. 15-LO-1 was most abundant in the heart; therefore, we used the Langendorff heart model to test the hypothesis that elevated 15-LO-1 levels would increase coronary flow following a short ischemia episode. Both peak flow and excess flow of reperfused hearts were significantly elevated in hearts from Tg compared to WT mice being 2.03 and 3.22 times greater, respectively. These results indicate that h15-LO-1-derived metabolites are highly vasoactive and may play a critical role in regulating coronary blood flow.

Citing Articles

Restoration of miR-223-3p expression in aged mouse uteri with Samul-tang administration.

Kim J, You S Integr Med Res. 2022; 11(2):100835.

PMID: 35141134 PMC: 8814392. DOI: 10.1016/j.imr.2022.100835.

(5Z,11Z,15R)-15-Hydroxyeicosa-5,11-dien-13-ynoic acid: A stable isomer of 15(S)-HETE that retains key vasoconstrictive and antiproliferative activity.

Pfister S, Klimko P, Conrow R Prostaglandins Other Lipid Mediat. 2016; 123:33-9.

PMID: 27117058 PMC: 4893888. DOI: 10.1016/j.prostaglandins.2016.04.001.

Overview of Antagonists Used for Determining the Mechanisms of Action Employed by Potential Vasodilators with Their Suggested Signaling Pathways.

Loh Y, Tan C, Chng Y, Ahmad M, Asmawi M, Yam M Molecules. 2016; 21(4):495.

PMID: 27092479 PMC: 6274436. DOI: 10.3390/molecules21040495.

Inhibition of soluble epoxide hydrolase increases coronary perfusion in mice.

Qin J, Sun D, Jiang H, Kandhi S, Froogh G, Hwang S Physiol Rep. 2015; 3(6).

PMID: 26071213 PMC: 4510629. DOI: 10.14814/phy2.12427.

Protection from hypertension in mice by the Mediterranean diet is mediated by nitro fatty acid inhibition of soluble epoxide hydrolase.

Charles R, Rudyk O, Prysyazhna O, Kamynina A, Yang J, Morisseau C Proc Natl Acad Sci U S A. 2014; 111(22):8167-72.

PMID: 24843165 PMC: 4050620. DOI: 10.1073/pnas.1402965111.

References

Cross H, Lu L, Steenbergen C, Philipson K, Murphy E . Overexpression of the cardiac Na+/Ca2+ exchanger increases susceptibility to ischemia/reperfusion injury in male, but not female, transgenic mice. Circ Res. 1998; 83(12):1215-23. DOI: 10.1161/01.res.83.12.1215. View

Hercule H, Schunck W, Gross V, Seringer J, Leung F, Weldon S . Interaction between P450 eicosanoids and nitric oxide in the control of arterial tone in mice. Arterioscler Thromb Vasc Biol. 2008; 29(1):54-60. DOI: 10.1161/ATVBAHA.108.171298. View

Zhang D, Gauthier K, Chawengsub Y, Campbell W . ACh-induced relaxations of rabbit small mesenteric arteries: role of arachidonic acid metabolites and K+. Am J Physiol Heart Circ Physiol. 2007; 293(1):H152-9. DOI: 10.1152/ajpheart.00268.2006. View

Matoba T, Shimokawa H, Nakashima M, Hirakawa Y, Mukai Y, Hirano K . Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice. J Clin Invest. 2000; 106(12):1521-30. PMC: 387255. DOI: 10.1172/JCI10506. View

Harats D, Kurihara H, Belloni P, Oakley H, Ziober A, Ackley D . Targeting gene expression to the vascular wall in transgenic mice using the murine preproendothelin-1 promoter. J Clin Invest. 1995; 95(3):1335-44. PMC: 441473. DOI: 10.1172/JCI117784. View

Campbell W, Spitzbarth N, Gauthier K, Pfister S . 11,12,15-Trihydroxyeicosatrienoic acid mediates ACh-induced relaxations in rabbit aorta. Am J Physiol Heart Circ Physiol. 2003; 285(6):H2648-56. DOI: 10.1152/ajpheart.00412.2003. View

Sakurai T, Yanagisawa M, Inoue A, Ryan U, Kimura S, Mitsui Y . cDNA cloning, sequence analysis and tissue distribution of rat preproendothelin-1 mRNA. Biochem Biophys Res Commun. 1991; 175(1):44-7. DOI: 10.1016/s0006-291x(05)81197-0. View

Brash A . Lipoxygenases: occurrence, functions, catalysis, and acquisition of substrate. J Biol Chem. 1999; 274(34):23679-82. DOI: 10.1074/jbc.274.34.23679. View

Magnusson L, Lundqvist A, Asp J, Synnergren J, Johansson C, Palmqvist L . High expression of arachidonate 15-lipoxygenase and proinflammatory markers in human ischemic heart tissue. Biochem Biophys Res Commun. 2012; 424(2):327-30. DOI: 10.1016/j.bbrc.2012.06.117. View

10.

Chauhan S, Nilsson H, Ahluwalia A, Hobbs A . Release of C-type natriuretic peptide accounts for the biological activity of endothelium-derived hyperpolarizing factor. Proc Natl Acad Sci U S A. 2003; 100(3):1426-31. PMC: 298789. DOI: 10.1073/pnas.0336365100. View

11.

Harats D, Ben-Shushan D, Cohen H, Gonen A, Barshack I, Goldberg I . Inhibition of carcinogenesis in transgenic mouse models over-expressing 15-lipoxygenase in the vascular wall under the control of murine preproendothelin-1 promoter. Cancer Lett. 2005; 229(1):127-34. DOI: 10.1016/j.canlet.2005.02.017. View

12.

De Marzo N, Sloane D, Dicharry S, Highland E, Sigal E . Cloning and expression of an airway epithelial 12-lipoxygenase. Am J Physiol. 1992; 262(2 Pt 1):L198-207. DOI: 10.1152/ajplung.1992.262.2.L198. View

13.

Harats D, Shaish A, George J, Mulkins M, Kurihara H, Levkovitz H . Overexpression of 15-lipoxygenase in vascular endothelium accelerates early atherosclerosis in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2000; 20(9):2100-5. DOI: 10.1161/01.atv.20.9.2100. View

14.

Bryant R, BAILEY J . Rearrangement of 15-hydroperoxy-eicosatetraenoic acid (15-HPETE) during incubations with hemoglobin: a model for platelet lipoxygenase metabolism. Prog Lipid Res. 1981; 20:279-81. DOI: 10.1016/0163-7827(81)90055-2. View

15.

Shappell S, Olson S, Hannah S, Manning S, Roberts R, Masumori N . Elevated expression of 12/15-lipoxygenase and cyclooxygenase-2 in a transgenic mouse model of prostate carcinoma. Cancer Res. 2003; 63(9):2256-67. View

16.

Heintz A, Damm M, Brand M, Koch T, Deussen A . Coronary flow regulation in mouse heart during hypercapnic acidosis: role of NO and its compensation during eNOS impairment. Cardiovasc Res. 2007; 77(1):188-96. DOI: 10.1093/cvr/cvm014. View

17.

Sun D, Funk C . Disruption of 12/15-lipoxygenase expression in peritoneal macrophages. Enhanced utilization of the 5-lipoxygenase pathway and diminished oxidation of low density lipoprotein. J Biol Chem. 1996; 271(39):24055-62. View

18.

Kuhn H, Thiele B . Arachidonate 15-lipoxygenase. J Lipid Mediat Cell Signal. 1995; 12(2-3):157-70. DOI: 10.1016/0929-7855(95)00016-j. View

19.

Kayama Y, Minamino T, Toko H, Sakamoto M, Shimizu I, Takahashi H . Cardiac 12/15 lipoxygenase-induced inflammation is involved in heart failure. J Exp Med. 2009; 206(7):1565-74. PMC: 2715088. DOI: 10.1084/jem.20082596. View

20.

Pfister S, Spitzbarth N, Nithipatikom K, Edgemond W, Falck J, Campbell W . Identification of the 11,14,15- and 11,12, 15-trihydroxyeicosatrienoic acids as endothelium-derived relaxing factors of rabbit aorta. J Biol Chem. 1998; 273(47):30879-87. DOI: 10.1074/jbc.273.47.30879. View