Myogenic Akt Signaling Regulates Blood Vessel Recruitment during Myofiber Growth

Blood vessel recruitment is an important feature of normal tissue growth. Here, we examined the role of Akt signaling in coordinating angiogenesis with skeletal muscle hypertrophy. Hypertrophy of C2C12 myotubes in response to insulin-like growth factor 1 or insulin and dexamethasone resulted in a marked increase in the secretion of vascular endothelial growth factor (VEGF). Myofiber hypertrophy and hypertrophy-associated VEGF synthesis were specifically inhibited by the transduction of a dominant-negative mutant of the Akt1 serine-threonine protein kinase. Conversely, transduction of constitutively active Akt1 increased myofiber size and led to a robust induction of VEGF protein production. Akt-mediated control of VEGF expression occurred at the level of transcription, and the hypoxia-inducible factor 1 regulatory element was dispensable for this regulation. The activation of Akt1 signaling in normal mouse gastrocnemius muscle was sufficient to promote myofiber hypertrophy, which was accompanied by an increase in circulating and tissue-resident VEGF levels and high capillary vessel densities at focal regions of high Akt transgene expression. In a rabbit hind limb model of vascular insufficiency, intramuscular activation of Akt1 signaling promoted collateral and capillary vessel formation and an accompanying increase in limb perfusion. These data suggest that myogenic Akt signaling controls both fiber hypertrophy and angiogenic growth factor synthesis, illustrating a mechanism through which blood vessel recruitment can be coupled to normal tissue growth

Regulation of rat liver apolipoprotein A-I, apolipoprotein A-II and acyl-coenzyme A oxidase gene expression by fibrates and dietary fatty acids

The regulation by fibrates and dietary fatty acids of the hepatic gene expression of apolipoproteins (apo) A-I and A-11, the major protein constituents of high-density lipoproteins, as well as of acyl-CoA oxidase, the rate-limiting enzyme of the peroxisomal P-oxidation pathway, was studied in vivu in the rat and in vitru in primary cultures of rat hepatocytes. In primary hepatocytes, different fibrates decreased apo A-I and increased acyl-CoA oxidase mRNA levels, whereas apo A-I1 mRNA only decreased in level after treatment with fenofibric acid, but not after bezafibrate, gemfibrozil or Wy-14643 treatment. Treat- ment with fenofibric acid counteracted the increase in apo A-I mRNA levels observed after dexametha- sone or all-trans retinoic acid treatment, whereas simultaneous addition of fenofibric acid together with all-trans retinoic acid or dexamethasone resulted in a superinduction of acyl-CoA oxidase mRNA. Addi- tion of the n-3 polyunsaturated fatty acids (PUFAs), docosanohexaenoic acid and eicosanopentaenoic acid, or the fatty acid derivative a-bromopalmitate, decreased apo A-I and increased acyl-CoA oxidase mRNA in a dose-dependent and time-dependent manner, whereas apo A-I1 mRNA did not change signifi- cantly. Nuclear run-on experiments demonstrated that fenofibric acid and a-bromopalmitate decreased apo A-I and increased acyl-CoA oxidase gene expression at the transcriptional level. When rats were fed isocaloric diets enriched in saturated fat (hydrogenated coconut oil), n-6 PUFAs (safflower oil) or n-3 PUFAs (fish oil), a significant decrease in liver apo A-I and apo A-I1 mRNA levels was only observed after fish oil feeding. Compared to feeding low fat, liver acyl-CoA oxidase mRNA increased after fat feeding, but this effect was most pronounced (twofold) in rats fed fish oil. Results from these studies indicate that fish oil feeding reduces rat liver apo A-I and apo A-I1 gene expression, similar to results obtained after feeding fenofibrate. Fibrates and n-3 fatty acids (and the fatty acid derivative, a-bromopal- mitate) down-regulate apo A-I and induce acyl-CoA oxidase gene expression through a direct transcrip- tional action on the hepatocyte. In contrast, only fenofibric acid, but not the other fibrates or fatty acids tested, decrease apo A-I1 gene expression in vitro

Adenovirus-mediated fibroblast growth factor 1 expression in the lung induces epithelial cell proliferation: consequences to hyperoxic lung injury in rats.

International audienceHigh concentrations of oxygen can induce pulmonary toxicity and cause injury to alveolar epithelial and endothelial cells. The present study was performed to determine whether the potent epithelial and endothelial fibroblast growth factor 1 (FGF-1) protected against hyperoxia-induced lung injury. Recombinant adenovirus carrying the gene encoding human secreted FGF-1 (Ad. FGF1) increased the proliferation of lung epithelial cells in vitro. Ad.FGF1 or control vector with an empty expression cassette (Ad.V152) was administered intratracheally to Wistar rats. With Ad.FGF1 (10(9), 5 x 10(9), 10(10), or 5 x 10(10) viral particles [VP]), FGF-1 protein was found in bronchoalveolar lavage fluid 4 days postinfection at levels proportional to the viral dose and was detected in plasma after doses of 10(10) VP or more were administered. Histological examination of the lungs showed intense proliferation and apoptosis of alveolar and bronchial epithelial cells, with few inflammatory cells. The alveolar architecture returned to normal within 17 days. Rats pretreated with Ad.FGF1 (10(9) or 5 x 10(9) VP) 2 days before exposure to hyperoxia (95% O2) survived, whereas rats pretreated with Ad.V152 died within 3 days. In conclusion, adenovirus-mediated FGF-1 overexpression in the lungs causes epithelial cell proliferation and has beneficial effects in hyperoxic lung injury