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ATPase inhibitory factor 1 protects the heart from acute myocardial ischemia/reperfusion injury through activating AMPK signaling pathway.

ABSTRACT: Rationale: Myocardial ischemia/reperfusion (I/R) injury is a common clinic scenario that occurs in the context of reperfusion therapy for acute myocardial infarction (AMI). The mitochondrial F1Fo-ATPase inhibitory factor 1 (IF1) blocks the reversal of the F1Fo-ATP synthase to prevent detrimental consumption of cellular ATP and associated demise. In the present study, we study the role and mechanism of IF1 in myocardial I/R injury. Methods: Mice were ligated the left anterior descending coronary artery to build the I/R model in vivo. Rat hearts were isolated and perfused with constant pressure according to Langendorff. Also, neonatal cardiomyocytes hypoxia-reoxygenation (H/R) model was also used. Myocardial infarction area, cardiac function, cellular function, and cell viability was conducted and compared. Results: Our data revealed that IF1 is upregulated in hearts after I/R and cardiomyocytes with hypoxia/re-oxygenation (H/R). IF1 delivered with adenovirus and adeno-associated virus serotype 9 (AAV9) ameliorated cardiac dysfunction and pathological development induced by I/R ex vivo and in vivo. Mechanistically, IF1 stimulates glucose uptake and glycolysis activity and stimulates AMPK activation during in vivo basal and I/R and in vitro OGD/R conditions, and activation of AMPK by IF1 is responsible for its cardioprotective effects against H/R-induced injury. Conclusions: These results suggest that increased IF1 in the I/R heart confer cardioprotective effects via activating AMPK signaling. Therefore, IF1 can be used as a potential therapeutic target for the treatment of pathological ischemic injury and heart failure.

SUBMITTER: Wu JW

PROVIDER: S-EPMC8741848 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RationaleAMPK (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.ObjectiveWe 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 resultsWe 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.ConclusionsThe 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.

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ATPase inhibitory factor 1 protects the heart from acute myocardial ischemia/reperfusion injury through activating AMPK signaling pathway.

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