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Cardiac-specific overexpression of CYP2J2 attenuates diabetic cardiomyopathy in male streptozotocin-induced diabetic mice
- Source :
- Endocrinology. 154(8)
- Publication Year :
- 2013
-
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.
- Subjects :
- Epoxygenase
Blood Glucose
Male
medicine.medical_specialty
Diabetic Cardiomyopathies
medicine.medical_treatment
Glucose uptake
Blotting, Western
Mice, Transgenic
Protein Serine-Threonine Kinases
Cytochrome P-450 CYP2J2
Cell Line
Diabetes Mellitus, Experimental
Mice
Endocrinology
Insulin resistance
Cytochrome P-450 Enzyme System
Diabetic cardiomyopathy
Diabetes mellitus
Internal medicine
medicine
Animals
Humans
Insulin
Glucose tolerance test
Glucose Transporter Type 4
biology
medicine.diagnostic_test
Myosin Heavy Chains
Reverse Transcriptase Polymerase Chain Reaction
Myocardium
Renal-Cardiac-Vascular
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Glucose Tolerance Test
medicine.disease
Lipids
Mice, Inbred C57BL
Insulin receptor
Gene Expression Regulation
Echocardiography
biology.protein
Insulin Resistance
Subjects
Details
- ISSN :
- 19457170
- Volume :
- 154
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Endocrinology
- Accession number :
- edsair.doi.dedup.....3222300ee425a7faeb58552baffe333b