Effect of caloric restriction on liver function in young and old ApoE/LDLr-/- mice

Background: Caloric restriction (CR) leads to decrease metabolic intensity, which results in a reduction of oxygen consumption and the amount of free radicals. This can affect the function of the liver. Studies show that caloric restriction does not alter or significantly increase the enzyme activity associated with gluconeogenesis, but the effect was different according to the age of the model animals. Objective: The aim of the study was to determine the effect of caloric restriction on liver function in young and old ApoE/ LDLr-/- mice. Material and methods: Dietary experiments were performed on 2 and 5 month old male ApoE/LDLr-/- mice. Animals were divided into 3 experimental groups (n=6) and fed AIN'93G diet for 8 and 5 weeks, respectively. Control animals were fed ad libitum (AL) and housed in a colony cages. These animals were checked for dietary intake. The second group were also fed ad libitum but the animals were kept individually in cages (stress AL- sAL). Similarly to sAL group, the animals from the CR group were kept individually but received a 30% less diet compared to AL group. At the end of the experiment animals were euthanized and the blood, liver and adipose tissue have been collected. Alanine aminotransferase (ALT) as well as aspartate aminotransferase (AST) were measured in plasma. Fatty acid profile was evaluated (relative %) in adipose tissue (GC-MS). Liver's stetosis was assessed. Results were analyzed statistically (ANOVA, STATISTICA v.10.0). Results: CR ApoE/LDLr-/- mice showed significantly lower body weight compared to animals, both AL and sAL. There were no significant differences between ALT and AST in both younger and older animals. However, negative tendencies were more pronounced in younger animals. In young animals CR significantly increased liver weight compared to AL (4.14 vs 3.73g/100g). In adipose tissue fatty acid profile differed in CR mice compared to control in young animals. Conclusions: Caloric restriction did not affect liver enzymes in mice. Caloric restriction showed similar but not identical metabolic activity in young and old mice.

Comprehensive MRI for the detection of subtle alterations in diastolic cardiac function in apoE/LDLR(-/-) mice with advanced atherosclerosis.

ApoE/LDLR(-/-) mice represent a reliable model of atherosclerosis. However, it is not clear whether cardiac performance is impaired in this murine model of atherosclerosis. Here, we used MRI to characterize cardiac performance in vivo in apoE/LDLR(-/-) mice with advanced atherosclerosis. Six-month-old apoE/LDLR(-/-) mice and age-matched C57BL/6J mice (control) were examined using highly time-resolved cine-MRI [whole-chamber left ventricle (LV) imaging] and MR tagging (three slices: basal, mid-cavity and apical). Global and regional measures of cardiac function included LV volumes, kinetics, time-dependent parameters, strains and rotations. Histological analysis was performed using OMSB (orceine with Martius, Scarlet and Blue) and ORO (oil red-O) staining to demonstrate the presence of advanced coronary atherosclerosis. MR-tagging-based strain analysis in apoE/LDLR(-/-) mice revealed an increased frequency of radial and circumferential systolic stretch (25% and 50% of segments, respectively, p ≤ 0.012), increased radial post-systolic strain index (45% of segments, p = 0.009) and decreased LV untwisting rate (-30.3° (11.6°)/cycle, p = 0.004) when compared with control mice. Maximal strains and LV twist were unchanged. Most of the cine-MRI-based LV functional and anatomical parameters also remained unchanged in apoE/LDLR(-/-) mice, with only a lower filling rate, longer filling time, shorter isovolumetric contraction time and slower heart rate observed in comparison with control mice. The coronary arteries displayed severe atherosclerosis, as evidenced by histological analysis. Using comprehensive MRI methods, we have demonstrated that, despite severe coronary atherosclerosis in six-month-old apoE/LDLR(-/-) mice, cardiac performance including global parameters, twist and strains, was well preserved. Only subtle diastolic alterations, possibly of ischemic background, were uncovered. Copyright © 2016 John Wiley & Sons, Ltd.

Compound Danshen Dripping Pill inhibits hypercholesterolemia/atherosclerosis-induced heart failure in ApoE and LDLR dual deficient mice via multiple mechanisms.

Heart failure is the leading cause of death worldwide. Compound Danshen Dripping Pill (CDDP) or CDDP combined with simvastatin has been widely used to treat patients with myocardial infarction and other cardiovascular diseases in China. However, the effect of CDDP on hypercholesterolemia/atherosclerosis-induced heart failure is unknown. We constructed a new model of heart failure induced by hypercholesterolemia/atherosclerosis in apolipoprotein E (ApoE) and LDL receptor (LDLR) dual deficient (ApoE-/-LDLR-/-) mice and investigated the effect of CDDP or CDDP plus a low dose of simvastatin on the heart failure. CDDP or CDDP plus a low dose of simvastatin inhibited heart injury by multiple actions including anti-myocardial dysfunction and anti-fibrosis. Mechanistically, both Wnt and lysine-specific demethylase 4A (KDM4A) pathways were significantly activated in mice with heart injury. Conversely, CDDP or CDDP plus a low dose of simvastatin inhibited Wnt pathway by markedly up-regulating expression of Wnt inhibitors. While the anti-inflammation and anti-oxidative stress by CDDP were achieved by inhibiting KDM4A expression and activity. In addition, CDDP attenuated simvastatin-induced myolysis in skeletal muscle. Taken together, our study suggests that CDDP or CDDP plus a low dose of simvastatin can be an effective therapy to reduce hypercholesterolemia/atherosclerosis-induced heart failure.

Compound Danshen Dripping Pill inhibits hypercholesterolemia/atherosclerosis-induced heart failure in ApoE and LDLR dual deficient mice via multiple mechanisms

Heart failure is the leading cause of death worldwide. Compound Danshen Dripping Pill (CDDP) or CDDP combined with simvastatin has been widely used to treat patients with myocardial infarction and other cardiovascular diseases in China. However, the effect of CDDP on hypercholesterolemia/atherosclerosis-induced heart failure is unknown. We constructed a new model of heart failure induced by hypercholesterolemia/atherosclerosis in apolipoprotein E (ApoE) and LDL receptor (LDLR) dual deficient (ApoE-/-LDLR-/-) mice and investigated the effect of CDDP or CDDP plus a low dose of simvastatin on the heart failure. CDDP or CDDP plus a low dose of simvastatin inhibited heart injury by multiple actions including anti-myocardial dysfunction and anti-fibrosis. Mechanistically, both Wnt and lysine-specific demethylase 4A (KDM4A) pathways were significantly activated in mice with heart injury. Conversely, CDDP or CDDP plus a low dose of simvastatin inhibited Wnt pathway by markedly up-regulating expression of Wnt inhibitors. While the anti-inflammation and anti-oxidative stress by CDDP were achieved by inhibiting KDM4A expression and activity. In addition, CDDP attenuated simvastatin-induced myolysis in skeletal muscle. Taken together, our study suggests that CDDP or CDDP plus a low dose of simvastatin can be an effective therapy to reduce hypercholesterolemia/atherosclerosis-induced heart failure.