TY - JOUR
T1 - Effect of human 15-lipoxygenase-1 metabolites on vascular function in mouse mesenteric arteries and hearts
AU - Kriska, Tamas
AU - Cepura, Cody
AU - Siangjong, Lawan
AU - Wan, Tina C.
AU - Auchampach, John A.
AU - Shaish, Aviv
AU - Haratz, Dror
AU - Kumar, Ganesh
AU - Falck, J R
AU - Gauthier, Kathryn M.
AU - Campbell, William B.
N1 - Funding Information:
The authors thank Ms. Devora Magier and Ms. Chuely Vang for their technical assistance and Ms. Gretchen Barg for her secretarial assistance. These studies were supported by grants from the National Heart, Lung and Blood Institute ( HL-37981 and HL-103673 ), the Robert A. Welch Foundation ( GL625910 ), and National Institute of General Medical Sciences ( GM-31278 ).
PY - 2013
Y1 - 2013
N2 - 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 [14C]-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.
AB - 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 [14C]-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.
KW - 15-Lipoxygenase
KW - Coronary flow
KW - Eicosanoids
KW - Endothelium-derived hyperpolarizing factor
KW - Ischemia/ reperfusion
KW - Reactive hyperemia
KW - Vasodilation
UR - http://www.scopus.com/inward/record.url?scp=84883361018&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84883361018&partnerID=8YFLogxK
U2 - 10.1016/j.prostaglandins.2013.07.002
DO - 10.1016/j.prostaglandins.2013.07.002
M3 - Article
C2 - 23872364
AN - SCOPUS:84883361018
SN - 1098-8823
VL - 106
SP - 8
EP - 15
JO - Journal of Lipid Mediators and Cell Signalling
JF - Journal of Lipid Mediators and Cell Signalling
IS - 1
ER -