Poster 5
Presenter: Michal Pravenec
Wednesday, 3:00 – 5:00pm

Loss-of-function mutation in endonuclease G (Endog) is associated with metabolic disturbances and oxidative stress in the SHR

Michal Pravenec¹, Vaclav Zidek¹, Vladimir Landa¹, Petr Mlejnek¹, Ludmila Kazdova², Olena Oliyarnyk², Josef Houstek¹, Hana Nuskova¹, Zdenek Drahota¹, Stuart Cook^3
1Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic; ²Institute for Clinical and Experimental Medicine, Prague, Czech Republic; ³Imperial College, London, United Kingdom

Recently, loss-of-function mutation in endonuclease G (Endog) has been identified as a genetic determinant of increased left vetricular mass and impaired mitochondrial function in the spontaneously hypertensive rat (SHR). In the current study, we analyzed the effects of mutant Endog on parameters of lipid and glucose metabolism, oxidative stress, and mitochondrial function in the SHR vs. SHR.BN congenic strain with wild type Endog. Four month old SHR males compared to age-matched SHR-Endog congenic rats exhibited changes in mitochondrial membrane potential and respiratory control index (RCI) in left vetricles indicating lower efficiency of oxidative phosphorylation. The SHR showed increased adiposity (relative weight of epididymal fat, ectopic fat accumulation in liver and heart), and higher serum triglyceride and NEFA levels. Adipose and muscle tissues in the SHR were resistant to insulin action when compared to congenic rats. In addition, SHR had significantly reduced palmitate oxidation in brown adipose tissue. These metabolic disturbances were associated with significantly increased oxidative stress when activities of antioxidant enzymes were reduced and concentrations of lipoperoxidation products were increased in SHR hearts and kidneys when compared to congenic rats. These results provide compelling evidence that mutant Endog is a novel determinant of metabolic disturbances in the SHR.