Double knockout of Akt2 and AMPK accentuates high fat diet-induced cardiac anomalies through a cGAS-STING-mediated mechanism.

Abstract

High fat diet intake contributes to undesired cardiac geometric and functional changes although the underlying mechanism remains elusive. Akt and AMPK govern to cardiac homeostasis. This study examined the impact of deletion of Akt2 (main cardiac isoform of Akt) and AMPKα2 on high fat diet intake-induced cardiac remodeling and contractile anomalies and mechanisms involved. Cardiac geometry, contractile, and intracellular Ca2+ properties were evaluated using echocardiography, IonOptix® edge-detection and fura-2 techniques in wild-type (WT) and Akt2-AMPK double knockout (DKO) mice receiving low fat (LF) or high fat (HF) diet for 4 months. Our results revealed that fat diet intake elicit obesity, cardiac remodeling (hypertrophy, LV mass, LVESD, and cross-sectional area), contractile dysfunction (fractional shortening, peak shortening, maximal velocity of shortening/relengthening, time-to-90% relengthening, and intracellular Ca2+ handling), ultrastructural disarray, apoptosis, O2-, inflammation, dampened autophagy and mitophagy. Although DKO did not affect these parameters, it accentuated high fat diet-induced cardiac remodeling and contractile anomalies. High fat intake upregulated levels of cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and STING phosphorylation while suppressing phosphorylation of ULK1 (Ser757 and Ser777), with a more pronounced effect in DKO mice. In vitro data revealed that inhibition of cGAS and STING using PF-06928215 and Astin C negated palmitic acid-induced cardiomyocyte contractile dysfunction. Biological function analysis for all differentially expressed genes (DEGs) depicted that gene ontology terms associated with Akt and AMPK signaling processes were notably changed in high fat-fed hearts. Our data indicate that Akt2-AMPK ablation accentuated high fat diet-induced cardiac anomalies possibly through a cGAS-STING-mechanism.

• Authors: Yan Gong, Guangwei Li, Jun Tao, Ne N Wu, Machender R Kandadi, Yaguang Bi, Shuyi Wang, Zhaohui Pei, Jun Ren
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1866 Issue 10 Pg. 165855 (10 01 2020) ISSN: 1879-260X [Electronic] Netherlands
• PMID: 32512189 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Membrane Proteins
• Sting1 protein, mouse
• AMPK alpha2 subunit, mouse
• Akt2 protein, mouse
• Proto-Oncogene Proteins c-akt
• AMP-Activated Protein Kinases
• Nucleotidyltransferases
• cGAS protein, mouse

Topics

• AMP-Activated Protein Kinases (genetics, metabolism)
• Animals
• Autophagy (genetics, immunology)
• Diet, High-Fat (adverse effects)
• Disease Models, Animal
• Humans
• Hypertrophy, Left Ventricular (etiology, immunology, metabolism, pathology)
• Membrane Proteins (metabolism)
• Mice
• Mice, Knockout
• Mitochondria (pathology)
• Mitophagy (genetics, immunology)
• Myocardium (cytology, immunology, pathology)
• Myocytes, Cardiac (cytology, pathology)
• Nucleotidyltransferases (metabolism)
• Obesity (etiology, immunology, metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Ventricular Remodeling (genetics)