Abstract Cholesterol-lowering statins have been shown to anticancer effects in different models and sensitize human tumor cells cytostatic drugs. We investigated the effect of on Akt/protein kinase B signaling sensitizing It was found that insulin– drug–induced Akt phosphorylation nuclear translocation inhibited by pravastatin atorvastatin HepG2, A549, H1299 an mTOR-dependent manner. Statins also induced insulin receptor substrate 1. In p53 wild-type (HepG2 A549), pretreatment with did not...

With a remarkable plasticity, skeletal muscle adapts to an altered functional demand. Muscle angio-adaptation can either involve the growth or regression of capillaries as respectively observed in response endurance training unloading. Whereas molecular mechanisms that regulate exercise-induced angiogenesis have been extensively studied, understanding how unloading contrast lead capillary has received very little attention. Here we investigated consequences 9 day time course hindlimb on both...

Impaired angiogenesis is a hallmark of metabolically dysfunctional adipose tissue in obesity. However, the underlying mechanisms restricting within this context remain ill-defined. Here, we demonstrate that induced endothelial-specific depletion transcription factor Forkhead Box O1 (FoxO1) male mice led to increased vascular density tissue. Upon high-fat diet feeding, endothelial cell FoxO1-deficient exhibited even greater remodeling visceral depot, which was paralleled with healthier...

Background: Impaired capillary growth (angiogenesis) in skeletal muscle and adipose tissue contributes to the development of metabolic disorders obese males. This association remains unexplored females, despite mounting evidence that endothelial cells have sex-specific transcriptional profiles. Therefore, herein we assessed whether males females show distinct angiogenic capacities response diet-induced obesity. Methods: Age-matched male female mice were fed normal chow or high-fat obesogenic...

The impaired skeletal muscle of chronic obstructive pulmonary disease (COPD) patients reduces exercise capacity. Similar to the oxidative fibres, angio-adaptation training may be blunted in these patients, as other conditions. We therefore compared functional responses and angio-adaptations after COPD sedentary healthy subjects (SHS). 24 (forced expiratory volume 1 s 45.6±17.5% predicted) 23 SHS (<150 min·week −1 moderate-to-vigorous exercise) completed a 6-week rehabilitation programme...

The angiostatic nature of pharmacological doses glucocorticoid steroids is well known. However, the consequences pathophysiological elevation endogenous glucocorticoids are not established. In current study, we hypothesized that effect corticosterone, an in rodents, occurs through multi-faceted alterations skeletal muscle microvascular endothelial cell proliferation, migration, and proteolysis. Chronic corticosterone treatment significantly reduced capillary to fiber ratio tibialis anterior...

Mdm2 inactivates the tumor suppressor p53 and Akt has been shown to be a major activator of in many cell types. We have investigated regulation hepatocytes. found that growth factor-induced Ser-166 phosphorylation was inhibited by MEK inhibitors U0126 PD98059 HepG2 cells rat liver line, TRL 1215. Also, bile acids oxidative stress induced at an apparently MEK-ERK-dependent mechanism. In contrast, lung mediated Akt. Further studies revealed phosphatidylinositol 3-kinase LY294002 wortmannin...

Key points The growth of new capillaries, angiogenesis, within skeletal muscle occurs only after weeks repeated aerobic exercise. Paradoxically, large increases in pro‐angiogenic factors such as vascular endothelial factor occur with a single exercise bout. mechanisms underlying the substantial lag angiogenic response remain to be elucidated. We detected concomitant angiostatic Forkhead Box ‘O’ transcription FoxO1 and FoxO3a matrix protein thrombospondin‐1 following bout exercise, but these...

3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors, statins, are widely used cholesterol-lowering drugs and have been shown to anticancer effects in many models. We investigated the effect of statins on Mdm2, a p53-specific ubiquitin ligase. It was found that pravastatin induced Mdm2 phosphorylation at Ser166 2A10 antibody-specific epitopes HepG2 cells, while mRNA levels were unchanged. Furthermore, induce mTOR Ser2448. abrogated by an inhibitor mTOR, rapamycin, but not...

Exercise-induced angiogenesis is a key determinant of skeletal muscle function. Here, we investigated whether the E3 ubiquitin ligase murine double minute-2 (Mdm2) exerts proangiogenic function in exercised muscle. Mdm2 hypomorphic (Mdm2Puro/Δ7-9) mice have 60% reduction expression compared with that wild-type animals. Capillary staining on sections from Mdm2Puro/Δ7-9 sedentary or knockout background for p53 revealed deficiency resulted 20% capillary regression independently status. In...

Skeletal muscle microvascular dysfunction contributes to disease severity in type 2 diabetes. Recent studies indicate a role for Forkhead box O (FoxO) transcription factors modulating endothelial cell phenotype. We hypothesized that high-fat (HF) diet generates dysfunctional vascular niche through an increased expression of FoxO. FoxO1 protein (+130%) the skeletal capillaries from HF compared normal chow-fed mice. was significantly elevated cultured cells exposed saturated fatty acid...

Female mice display greater adipose angiogenesis and maintain healthier tissue than do males upon high-fat diet feeding. Through transcriptome analysis of endothelial cells (EC) from the white male female high-fat-fed for 7 weeks, we found that EC exhibited pronouncedly sex-distinct transcriptomes. Genes upregulated in were associated with proliferation, oxidative phosphorylation, chromatin remodeling contrasting dominant enrichment genes related to inflammation a senescence-associated...

Skeletal muscle capillarisation responds to physiological and pathological conditions with a remarkable plasticity. Angiomotin was recently identified as new pro-angiogenic molecule. is expressed two protein isoforms, p80 p130. Whereas stimulates endothelial cell migration angiogenesis, p130 rather characteristic of stabilized matured vessels. To date, how angiomotin expression physiologically regulated in vivo remains largely unknown. We thus investigated (1) whether skeletal muscle; (2)...

We demonstrated in a previous study that murine double minute (Mdm)-2 is essential for exercise-induced skeletal muscle angiogenesis. In the current study, we investigated mechanisms regulate Mdm2 activity response to acute exercise and identified VEGF-A as key stimulator of phosphorylation on Ser(166) (p-Ser166-Mdm2). p-Ser166-Mdm2 protein levels were measured human rodent biopsy specimens after 1 bout exercise. VEGF-A-dependent was vivo mice harboring myofiber-specific deletion...

Pyruvate is located at a crucial crossroad of cellular metabolism between the aerobic and anaerobic pathways. Modulation fate pyruvate, in one direction or another, can be important for adaptative response to hypoxia followed by reoxygenation. This could alter functioning antioxidant system have protective effects against DNA damage induced such stress. Transient alterations pyruvate are observed tumors. advantageous cancer cells stressful conditions. However, effect tumor poorly documented...

High expression levels of human double minute-2 (Hdm2) are often associated with increased risk cancer. Hdm2 is well established as an oncoprotein exerting various tumorigenic effects. Conversely, the physiological functions in nontumor cells and healthy tissues remain largely unknown. We previously demonstrated that exercise training stimulates murine (Mdm2), analog Hdm2, rodent skeletal muscle Mdm2 was required for exercise-induced angiogenesis. Here we showed stimulated protein from +38%...

Critical limb ischaemia (CLI) is characterized by inadequate angiogenesis, arteriolar remodelling and chronic myopathy, which are most severe in type 2 diabetic patients. Hypertriglyceridaemia, commonly observed these patients, compromises macrovascular function. However, the effects of high-fat diet-induced increases circulating lipids on microvascular not established. Here, we investigated if diet would mimic detrimental effect diabetes post-ischaemia vascular muscle regeneration, using a...