Opposite effects of gene deficiency and pharmacological inhibition of soluble epoxide hydrolase on cardiac fibrosis.
Arachidonic acid-derived epoxyeicosatrienoic acids (EETs) are important regulators of cardiac remodeling; manipulation of their levels is a potentially useful pharmacological strategy. EETs are hydrolyzed by soluble epoxide hydrolase (sEH) to form the corresponding diols, thus altering and reducing the activity of these oxylipins. To better understand the phenotypic impact of sEH disruption, we compared the effect of EPHX2 gene knockout (EPHX2-/-) and sEH inhibition in mouse models. Measurement of plasma oxylipin profiles confirmed that the ratio of EETs/DHETs was increased in EPHX2-/- and sEH-inhibited mice. However, plasma concentrations of 9, 11, 15, 19-HETE were elevated in EPHX2-/- but not sEH-inhibited mice. Next, we investigated the role of this difference in cardiac dysfunction induced by Angiotensin II (AngII). Both EPHX2 gene deletion and inhibition protected against AngII-induced cardiac hypertrophy. Interestingly, cardiac dysfunction was attenuated by sEH inhibition rather than gene deletion. Histochemical staining revealed that compared with pharmacological inhibition, EPHX2 deletion aggravated AngII-induced myocardial fibrosis; the mRNA levels of fibrotic-related genes were increased. Furthermore, cardiac inflammatory response was greater in EPHX2-/- than sEH-inhibited mice with AngII treatment, as evidenced by increased macrophage infiltration and expression of MCP-1 and IL-6. In vitro, AngII-upregulated MCP-1 and IL-6 expression was significantly attenuated by sEH inhibition but promoted by EPHX2 deletion in cardiofibroblasts. Thus, compared with pharmacological inhibition of sEH, EPHX2 deletion caused the shift in arachidonic acid metabolism, which may led to pathological cardiac remodeling, especially cardiac fibrosis.
Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.
Lijuan
L
Li
Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.
Nan
N
Li
Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.
Wei
W
Pang
Department of Physiology, Tianjin Medical University, Tianjin, China.
Xu
X
Zhang
Department of Entomology and Comprehensive Cancer Center, University of California Davis, Davis, California, United States of America.
Bruce D
BD
Hammock
Department of Physiology, Tianjin Medical University, Tianjin, China.
Ding
D
Ai
Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China; Department of Physiology, Tianjin Medical University, Tianjin, China.
Yi
Y
Zhu
D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D001095:Arachidonic Acids / Q000378:metabolism*; D015415:Biomarkers; D006332:Cardiomegaly / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005355:Fibrosis; D006973:Hypertension / Q000139:chemically induced / Q000150:complications / Q000201:enzymology / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology*; D058628:Myofibroblasts / Q000201:enzymology; D020257:Ventricular Remodeling / Q000235:genetics / Q000502:physiology
D001095:Arachidonic Acids; D015415:Biomarkers; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D015850:Interleukin-6; C577686:interleukin-6, mouse; D000804:Angiotensin II; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse