title: Cardiac-specific overexpression of CYP2J2 attenuates diabetic cardiomyopathy in male streptozotocin-induced diabetic mice.
abstract: Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid to biologically active cis-epoxyeicosatrienoic acids, which have potent vasodilatory, antiinflammatory, antiapoptotic, and antidiabetes properties. Here, we showed the effects of cardiac-specific overexpression of CYP epoxygenase 2J2 (CYP2J2) on diabetic cardiomyopathy and insulin resistance in high-fat (HF) diet fed, low-dose streptozotocin-treated mice. Diabetic cardiomyopathy was induced by HF and streptozotocin in cardiac-specific CYP2J2 transgenic mice. Physiological parameters and systemic metabolic parameters were monitored using ELISA kits. Intraperitoneal injection glucose tolerance test and hyperinsulinemic-euglycemic clamp study were implied to indicate insulin resistance. Cardiac function was assessed by echocardiography and Millar catheter system. Real-time PCR and Western blotting were used in signal pathway detection. αMHC-CYP2J2 transgenic mice showed significantly lower plasma glucose and insulin levels, improved glucose tolerance, and increased cardiac glucose uptake. Furthermore, αMHC-CYP2J2 transgenic mice were significantly protected from HF-streptozotocin-induced diabetic cardiomyopathy. Strikingly, CYP2J2 overexpression attenuated myocardial hypertrophy induced by diabetes. We conclude that cardiac-specific overexpression of CYP2J2 significantly protects against diabetic cardiomyopathy, which may be due to improved cardiac insulin resistance, glucose uptake, and reversal of cardiac hypertrophy. Relevant mechanisms may include up-regulation of peroxisome proliferator-activated receptor γ, activation of insulin receptor and AMP-activated protein kinase signaling pathways, and inhibition of nuclear factor of activated T cells c3 signal by enhanced atrial natriuretic peptide production. These results suggest that CYP2J2 epoxygenase metabolites likely play an important role in plasma glucose homeostasis, and enhancement of epoxyeicosatrienoic acids activation may serve as an effective therapeutic strategy to prevent diabetic cardiomyopathy.
authors.affiliation: The Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China.
authors.forename: Ben
authors.initials: B
authors.lastname: Ma
authors.forename: Xiaojv
authors.initials: X
authors.lastname: Xiong
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Huaping
authors.initials: H
authors.lastname: Li
authors.forename: Xizhen
authors.initials: X
authors.lastname: Xu
authors.forename: Xuguang
authors.initials: X
authors.lastname: Li
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Chen
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Dackor
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000235:genetics*; D058065:Diabetic Cardiomyopathies / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D004452:Echocardiography; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001786:Blood Glucose; C000717350:CYP2J2 protein, human; D051275:Glucose Transporter Type 4; D007328:Insulin; D008055:Lipids; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C495693:Slc2a4 protein, mouse; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2; D017346:Protein Serine-Threonine Kinases; D018995:Myosin Heavy Chains