| First Author | Cao Y | Year | 2017 |
| Journal | Circ Res | Volume | 121 |
| Issue | 10 | Pages | 1182-1191 |
| PubMed ID | 28835357 | Mgi Jnum | J:341591 |
| Mgi Id | MGI:6880892 | Doi | 10.1161/CIRCRESAHA.117.311159 |
| Citation | Cao Y, et al. (2017) Activation of gamma2-AMPK Suppresses Ribosome Biogenesis and Protects Against Myocardial Ischemia/Reperfusion Injury. Circ Res 121(10):1182-1191 |
| abstractText | 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 gamma2-AMPK in cardiac stress response using bioengineered cell lines and mouse models containing either isoform of the gamma-subunit in the heart. METHODS AND RESULTS: We found that gamma2 but not gamma1 or gamma3 subunit translocated into nucleus on AMPK activation. Nuclear accumulation of AMPK complexes containing gamma2-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 gamma2-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 gamma2-AMPK in the heart, we generated a mouse model with cardiac-specific deletion of gamma2-AMPK (cardiac knockout [cKO]). Although the total AMPK activity was unaltered in cKO hearts because of upregulation of gamma1-AMPK, the lack of gamma2-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 gamma2-AMPK decreased ribosome biosynthesis and ER stress during ischemia/reperfusion insult, and the infarct size was reduced. CONCLUSIONS: The gamma2-AMPK translocates into the nucleus to suppress pre-rRNA transcription and ribosome biosynthesis during stress, thus ameliorating ER stress and cell death. Increased gamma2-AMPK activity is required to protect against ischemia/reperfusion injury. Our study reveals an isoform-specific function of gamma2-AMPK in modulating ribosome biosynthesis, cell survival, and cardioprotection. |
