Abstract
Background: Obesity and diabetes are independently associated with the development of cardiac events that occur in db mice that are linked to a decrease in heme oxygenase-1 (HO-1) and epoxyeicosatrienoics (EETs). An increase in HO-1 and EET levels is associated with a decrease of ROS, adiposity and increased mitochondrial function in several animal models. The roles and inter-relationship of HO-1, EET, and PGC-1α in cardiomyopathy pathogenesis has not been investigated. Methods: Obese (db) mice 5 wks of age were allowed to acclimate for 17 wks, and then divided into 3 groups. A) Control, B) EET-A in drinking water, and C) EET-A and lentiviral (Ln) PGC-1α Sh, which decreased PGC1α by 40-60 %. Echocardiography was performed at 5 and 34 wks, serum and heart tissue were harvested to measure signaling and mitochondrial fusion proteins. Results: Group A) developed hyperglycemia, insulin resistance, and LV dysfunction. These changes were associated with decreases in PGC-1α, HO-1, MnSOD, and mitochondrial fusion associated proteins; Mfn 1/2 and OPA-1: Group B), received EET-A, and displayed normal levels of glucose, adipose adiponectin (p<0.05), insulin sensitivity, and increased levels of HO-1, PGC1α (p<0.02), insulin receptor phosphorylation (p<0.05), and Mfn 1/2 and OPA1 (p<0.001) when compared to normal levels of young (5 wks) db mice, before the development of cardiomyopathy: and group C) inhibition of PGC1α by Ln-PGC1- (Sh) prevented EET from restoring LV function and fractional shortening (p<0.05) EET-A- Ln-PGC1α (Sh) animals display a worsening of intrinsic myocardial contraction compared to db control. This is likely related to a decrease in the cardiac mitochondrial network. The latter was reciprocally correlated to HO-1-PGC1α levels that diminished as obesity/diabetes progressed. Conclusion: An EET-A agonist ameliorates adiposity, BP elevation, mitochondrial function and cardiomyopathy as a result of increased levels of PGC1α and HO-1-expression. Suppression of PGC1α by Ln PGC1α (Sh) worsened insulin resistance suggesting targeting mitochondrial fusion/fission may be a promising therapy for diabetes and heart disease.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
