Cardiac-specific deletion of γ2-AMPK increased infarct size during ischemia/reperfusion, whereas its overexpression decreased ribosome biosynthesis, ER stress, and infarct size.
Does γ2-AMPK deletion or overexpression affect infarct size and cell survival during myocardial ischemia/reperfusion injury in mouse models?
The γ2-AMPK isoform plays a unique, cardioprotective role during ischemia/reperfusion injury by translocating to the nucleus to suppress ribosome biogenesis and attenuate ER stress.
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 γ2-AMPK in cardiac stress response using bioengineered cell lines and mouse models containing either isoform of the γ-subunit in the heart. METHODS AND RESULTS: We found that γ2 but not γ1 or γ3 subunit translocated into nucleus on AMPK activation. Nuclear accumulation of AMPK complexes containing γ2-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 γ2-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 γ2-AMPK in the heart, we generated a mouse model with cardiac-specific deletion of γ2-AMPK (cardiac knockout cKO). Although the total AMPK activity was unaltered in cKO hearts because of upregulation of γ1-AMPK, the lack of γ2-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 γ2-AMPK decreased ribosome biosynthesis and ER stress during ischemia/reperfusion insult, and the infarct size was reduced. CONCLUSIONS: The γ2-AMPK translocates into the nucleus to suppress pre-rRNA transcription and ribosome biosynthesis during stress, thus ameliorating ER stress and cell death. Increased γ2-AMPK activity is required to protect against ischemia/reperfusion injury. Our study reveals an isoform-specific function of γ2-AMPK in modulating ribosome biosynthesis, cell survival, and cardioprotection.
Cao et al. (Thu,) conducted a other in Myocardial ischemia/reperfusion injury. γ2-AMPK deletion or overexpression vs. Wild-type or control was evaluated on Infarct size, ER stress, and cell death. Cardiac-specific deletion of γ2-AMPK increased infarct size during ischemia/reperfusion, whereas its overexpression decreased ribosome biosynthesis, ER stress, and infarct size.