Jelenik 2013 Eur Heart J
|Jelenik T, Floegel U, Phielix E, Kaul K, Nowotny P, Partke HP, Schrader J, Roden M, Szendroedi S (2013) Non-alcoholic fatty liver disease and insulin resistance are associated with increased cardiac oxidative stress in mice. Eur Heart J 34:P5045.|
Abstract: Diabetic cardiomyopathy has been related to reduced oxidative capacity and increased oxidative stress in cardiomyocytes. Non-alcoholic fatty liver (NAFL) and insulin resistance are associated with increased cardiovascular risk and cardiac mortality. We investigated how NAFL and insulin resistance relate to cardiac oxidative stress and mitochondrial oxidative capacity in mice.
Female mice, aged 18 and 36 weeks (w), with adipose tissue-specific overexpression of the sterol regulatory-element binding protein-1c (aP2-SREBP-1c: AP2), a model of NAFL, and wild-type controls (CON) underwent hyperinsulinemic-euglycemic clamps to assess insulin sensitivity (n=5-7). Mitochondrial respiration and reactive oxygen species production from isolated mitochondria were assessed by high-resolution respirometry and Amplex Red method, respectively (n=4). Cardiac morphology and function were measured in vivo by NMR imaging in 36-weeks old mice (n=8).
Whole body insulin sensitivity was 71% and 70% lower in both 18- and 36-weeks old AP2 mice than in aged-matched CON (p<0.05). Ex vivo cardiac mitochondrial oxidative capacity on tricarboxylic acid cycle-derived substrates was unchanged in 18 w old, but 93% higher in 36 w old AP2 mice (state u respiration: 2.86±0.06, CON: 1.47±0.43 nmol/mg protein/s; p<0.05). Oxidative capacity on β-oxidation-derived substrates was 60% and 125% greater in 18 w old (2.18±0.22, CON: 1.36±0.19; p<0.05) and 36 w old (2.45±0.66, CON: 1.09±0.22 nmol/mg protein/s; p<0.05) AP2 mice, respectively. H2O2 production by mitochondrial complex III was 51% higher (p<0.05) only in 36 w old mice, compared to age-matched CON. There was a 34% increase in left ventricular mass and 21% increase in wall thickness (p<0.001) suggesting myocardial hypertrophy in AP2 mice. Finally, older AP2 mice had 24% greater stroke volume and 29% higher cardiac output (for both p<0.05 vs. CON). Data were analyzed by two-tailed unpaired t-tests, p<0.05 was considered significant.
Insulin resistance in a mouse model of hepatic steatosis associates with increased cardiac mitochondrial respiration and oxidative stress, which develop progressively with rising age. These changes are associated with left ventricle hypertrophy and increased cardiac output, which could reflect adaptation to either higher blood pressure or to increased substrate flux. Insulin resistance and steatosis may therefore lead to higher myocardial energy turnover and oxidative stress rendering the hearts vulnerable for ischemic intolerance and impaired myocardial function.
• O2k-Network Lab: DE Duesseldorf Roden M
Labels: MiParea: Respiration, Genetic knockout;overexpression, Exercise physiology;nutrition;life style
Stress:Oxidative stress;RONS Organism: Mouse Tissue;cell: Heart Preparation: Isolated mitochondria
HRR: Oxygraph-2k, O2k-Fluorometer