Dataset Information

Activation of ?2-AMPK Suppresses Ribosome Biogenesis and Protects Against Myocardial Ischemia/Reperfusion Injury.

ABSTRACT: RATIONALE:AMPK (AMP-activated protein kinase) is a heterotrimeric protein that plays an important role in energy homeostasis and cardioprotection. Two isoforms of each subunit are expressed in the heart, but the isoform-specific function of AMPK remains unclear. OBJECTIVE:We sought to determine the role of ?2-AMPK in cardiac stress response using bioengineered cell lines and mouse models containing either isoform of the ?-subunit in the heart. METHODS AND RESULTS:We found that ?2 but not ?1 or ?3 subunit translocated into nucleus on AMPK activation. Nuclear accumulation of AMPK complexes containing ?2-subunit phosphorylated and inactivated RNA Pol I (polymerase I)-associated transcription factor TIF-IA at Ser-635, precluding the assembly of transcription initiation complexes for rDNA. The subsequent downregulation of pre-rRNA level led to attenuated endoplasmic reticulum (ER) stress and cell death. Deleting ?2-AMPK led to increases in pre-rRNA level, ER stress markers, and cell death during glucose deprivation, which could be rescued by inhibition of rRNA processing or ER stress. To study the function of ?2-AMPK in the heart, we generated a mouse model with cardiac-specific deletion of ?2-AMPK (cardiac knockout [cKO]). Although the total AMPK activity was unaltered in cKO hearts because of upregulation of ?1-AMPK, the lack of ?2-AMPK sensitizes the heart to myocardial ischemia/reperfusion injury. The cKO failed to suppress pre-rRNA level during ischemia/reperfusion and showed a greater infarct size. Conversely, cardiac-specific overexpression of ?2-AMPK decreased ribosome biosynthesis and ER stress during ischemia/reperfusion insult, and the infarct size was reduced. CONCLUSIONS:The ?2-AMPK translocates into the nucleus to suppress pre-rRNA transcription and ribosome biosynthesis during stress, thus ameliorating ER stress and cell death. Increased ?2-AMPK activity is required to protect against ischemia/reperfusion injury. Our study reveals an isoform-specific function of ?2-AMPK in modulating ribosome biosynthesis, cell survival, and cardioprotection.

SUBMITTER: Cao Y

PROVIDER: S-EPMC5659937 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Activation of γ2-AMPK Suppresses Ribosome Biogenesis and Protects Against Myocardial Ischemia/Reperfusion Injury.

Cao Yang Y Bojjireddy Naveen N Kim Maengjo M Li Tao T Zhai Peiyong P Nagarajan Narayani N Sadoshima Junichi J Palmiter Richard D RD Tian Rong R

Circulation research 20170823 10

<h4>Rationale</h4>AMPK (AMP-activated protein kinase) is a heterotrimeric protein that plays an important role in energy homeostasis and cardioprotection. Two isoforms of each subunit are expressed in the heart, but the isoform-specific function of AMPK remains unclear.<h4>Objective</h4>We sought to determine the role of γ2-AMPK in cardiac stress response using bioengineered cell lines and mouse models containing either isoform of the γ-subunit in the heart.<h4>Methods and results</h4>We found t ...[more]

PMID: 28835357

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Project description:Mitochondrial dysfunction is a salient feature of myocardial ischemia/reperfusion injury (MIRI), while the potential mechanism of mitochondrial dynamics disorder remains unclear. This study sought to explore whether activation of Adenosine monophosphate-activated protein kinase (AMPK) could alleviate MIRI by regulating GTPase dynamin-related protein 1 (Drp1)-mediated mitochondrial dynamics. Isolated mouse hearts in a Langendorff perfusion system were subjected to ischemia/reperfusion (I/R) treatment, and H9C2 cells were subjected to hypoxia /reoxygenation (H/R) treatment in vitro. The results showed that AICAR, the AMPK activator, could significantly improve the function of left ventricular, decrease arrhythmia incidence and myocardial infarction area of isolated hearts. Meanwhile, AICAR increased superoxide dismutase (SOD) activity and decreased malondialdehyde (MDA) content in myocardial homogenate. Mechanistically, AICAR inhibited the phosphorylation of Drp1 at Ser 616 while enhanced phosphorylation of Drp1 at Ser 637. In addition, AICAR reduced the expression of inflammatory cytokines including TNF-ɑ, IL-6, and IL-1β, as well as mitochondrial fission genes Mff and Fis1, while improved the expression of mitochondrial fusion genes Mfn1 and Mfn2. Similar results were also observed in H9C2 cells. AICAR improved mitochondrial membrane potential (MMP), reduced reactive oxygen species (ROS) production, and inhibited mitochondrial damage. To further prove if Drp1 regulated mitochondrial dynamics mediated AMPK protection effect, the mitochondrial fission inhibitor Mdivi-1 was utilized. We found that Mdivi-1 significantly improved MMP, inhibited ROS production, reduced the expression of TNF-a, IL-6, IL-1β, Fis1, and Mff, and improved the expression of Mfn1 and Mfn2. However, the protection effect of Mdivi-1 was not reversed by AMPK inhibitor Compound C. In conclusion, this study confirmed that activation of AMPK exerted the protective effects on MIRI, which were largely dependent on the inhibition of Drp1-mediated mitochondrial fission.

Project description:Background:Oxidative stress is a major contributor to the onset and development of myocardial ischemia reperfusion injury (MIRI). Sappanone A (SA), a homoisoflavanone extracted from the heartwood of Caesalpinia sappan L., has been demonstrated to possess powerful antioxidant activity. Therefore, this study aimed to determine the protective effect of SA on MIRI and investigate its underlying mechanism. Methods:The rat hearts were isolated and underwent 30-min ischemia, followed by 120-min reperfusion to establish the MIRI model, using the Langendorff method. SA was administrated intraperitoneally into rats 1 h prior to heart isolation. The myocardial infarct size and apoptosis were measured by TTC and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Myocardial enzyme activity, MDA content and the activities of SOD and GSH-Px were detected by colorimetric spectrophotometric method. Reactive oxygen species (ROS) level was detected by DCFH-DA probe. The change in Keap1/Nrf2 signaling pathway was evaluated by Western blotting. Results:SA reduced myocardial infarct size and the release of CK-MB and LDH in a dose-dependent manner. Moreover, SA improved the recovery of cardiac function, inhibited MIRI-induced apoptosis, repressed the production of ROS and MDA, and enhanced the activities of SOD and GSH-Px. Mechanistically, SA downregulated Keap1, induced Nrf2 nuclear accumulation, and enhanced Nrf2 transcriptional activity, subsequently resulting in an increase in the expression of the Nrf2 target genes heme oxygenase-1 and NAD(P)H quinone dehydrogenase 1. Moreover, SA enhanced the phosphorylation of Nfr2, but the enhancement in Nfr2 phosphorylation was abrogated by PKC or PI3K inhibitor. Conclusion:Collectively, it was demonstrated that SA prevents MIRI via coordinating the cellular antioxidant defenses and maintaining the redox balance, by modulation of Nrf2 via the PKC or PI3K pathway. Therefore, SA was a potential therapeutic drug for treating MIRI.

Dataset Information

Activation of ?2-AMPK Suppresses Ribosome Biogenesis and Protects Against Myocardial Ischemia/Reperfusion Injury.

Publications

Activation of γ2-AMPK Suppresses Ribosome Biogenesis and Protects Against Myocardial Ischemia/Reperfusion Injury.

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