Dataset Information

Autophagy activation: a novel mechanism of atorvastatin to protect mesenchymal stem cells from hypoxia and serum deprivation via AMP-activated protein kinase/mammalian target of rapamycin pathway.

ABSTRACT: Autophagy is a complex "self-eating" process and could be utilized for cell survival under stresses. Statins, which could reduce apoptosis in mesenchymal stem cells (MSCs) during both ischemia and hypoxia/serum deprivation (H/SD), have been proved to induce autophagy in some cell lines. We have previously shown that atorvastatin (ATV) could regulate AMP-activated protein kinase (AMPK), a positive modulator of autophagy, in MSCs. Thus, we hypothesized that autophagy activation through AMPK and its downstream molecule mammalian target of rapamycin (mTOR) may be a novel mechanism of ATV to protect MSCs from apoptosis during H/SD. Here, we demonstrated that H/SD induced autophagy in MSCs significantly as identified by increasing acidic vesicular organelle-positive cells, type II of light chain 3 (LC3-II) expression, and autophagosome formation. The levels of H/SD-induced apoptosis were increased by autophagy inhibitor 3-methyladenine (3-MA) while decreased by rapamycin, an autophagic inducer. ATV further enhanced the autophagic activity observed in MSCs exposed to H/SD. Treatment with 3-MA attenuated ATV-induced autophagy and abrogated the protective effects of ATV on MSC apoptosis, while rapamycin failed to cause additional effects on either autophagy or apoptosis compared with ATV alone. The phosphorylation of AMPK was upregulated whereas the phosphorylation of mTOR was downregulated in ATV-treated MSCs, which were both attenuated by AMPK inhibitor compound C. Further, treatment with compound C reduced the ATV-induced autophagy in MSCs under H/SD. These data suggest that autophagy plays a protective role in H/SD-induced apoptosis of MSCs, and ATV could effectively activate autophagy via AMPK/mTOR pathway to enhance MSC survival during H/SD.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC3353754 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Autophagy activation: a novel mechanism of atorvastatin to protect mesenchymal stem cells from hypoxia and serum deprivation via AMP-activated protein kinase/mammalian target of rapamycin pathway.

Zhang Qian Q Yang Yue-Jin YJ Wang Hong H Dong Qiu-Ting QT Wang Tian-Jie TJ Qian Hai-Yan HY Xu Hui H

Stem cells and development 20120328 8

Autophagy is a complex "self-eating" process and could be utilized for cell survival under stresses. Statins, which could reduce apoptosis in mesenchymal stem cells (MSCs) during both ischemia and hypoxia/serum deprivation (H/SD), have been proved to induce autophagy in some cell lines. We have previously shown that atorvastatin (ATV) could regulate AMP-activated protein kinase (AMPK), a positive modulator of autophagy, in MSCs. Thus, we hypothesized that autophagy activation through AMPK and it ...[more]

PMID: 22356678

Similar Datasets

Project description:AIMS:The abundance of beta 3-adrenergic receptors (?3-ARs) is upregulated in diseased human myocardium. We previously showed that cardiac-specific expression of ?3-AR inhibits the hypertrophic response to neurohormonal stimulation. Here, we further analysed signalling pathways involved in the anti-hypertrophic effect of ?3-AR. METHODS AND RESULTS:In vitro hypertrophic responses to phenylephrine (PE) were analysed in neonatal rat ventricular myocytes (NRVM) infected with a recombinant adenovirus expressing the human ?3-AR (AdVh?3). We confirmed results in mice with cardiomyocyte-specific moderate expression of human ?3-AR (?3-TG) and wild-type (WT) littermates submitted to thoracic transverse aortic constriction (TAC) for 9 weeks. We observed a colocalization of ?3-AR with the AMP-activated protein kinase (AMPK) both in neonatal rat and in adult mouse cardiomyocytes. Treatment of NRVM with PE induced hypertrophy and a decrease in phosphorylation of Thr172-AMPK (/2, P = 0.0487) and phosphorylation of Ser79-acetyl-CoA carboxylase (ACC) (/2.6, P = 0.0317), inducing an increase in phosphorylated Ser235/236 S6 protein (×2.5, P = 0.0367) known to be involved in protein synthesis. These effects were reproduced by TAC in WT mice but restored to basal levels in ?3-AR expressing cells/mice. siRNA targeting of AMPK partly abrogated the anti-hypertrophic effect of ?3-AR in response to PE in NRVM. Concomitant with hypertrophy, autophagy was decreased by PE, as measured by microtubule-associated protein 1 light chain 3 (LC3)-II/LC3-I ratio (/2.6, P = 0.0010) and p62 abundance (×3, P = 0.0016) in NRVM or by TAC in WT mice (LC3-II/LC3-I ratio: /5.4, P = 0.0159), but preserved in human ?3-AR expressing cells and mice, together with reduced hypertrophy. CONCLUSIONS:Cardiac-specific moderate expression of ?3-AR inhibits the hypertrophic response in part through AMPK activation followed by inhibition of protein synthesis and preservation of autophagy. Activation of the cardiac ?3-AR pathway may provide future therapeutic avenues for the modulation of hypertrophic remodelling.

Dataset Information

Autophagy activation: a novel mechanism of atorvastatin to protect mesenchymal stem cells from hypoxia and serum deprivation via AMP-activated protein kinase/mammalian target of rapamycin pathway.

Publications

Autophagy activation: a novel mechanism of atorvastatin to protect mesenchymal stem cells from hypoxia and serum deprivation via AMP-activated protein kinase/mammalian target of rapamycin pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets