Double knockout of Akt2 and AMPK accentuates high fat diet-induced cardiac anomalies through a cGAS-STING-mediated mechanism
| Autor: | Jun Ren, Zhaohui Pei, Guangwei Li, Machender R. Kandadi, Yaguang Bi, Yan Gong, Shuyi Wang, Ne N. Wu, Jun Tao |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Inflammation AKT2 030204 cardiovascular system & hematology AMP-Activated Protein Kinases Diet High-Fat Muscle hypertrophy 03 medical and health sciences Mice 0302 clinical medicine Internal medicine Mitophagy medicine Autophagy Animals Humans Myocytes Cardiac Obesity Phosphorylation Molecular Biology Protein kinase B Mice Knockout Ventricular Remodeling Chemistry Myocardium AMPK Membrane Proteins Nucleotidyltransferases Mitochondria Disease Models Animal 030104 developmental biology Endocrinology Molecular Medicine Hypertrophy Left Ventricular medicine.symptom Proto-Oncogene Proteins c-akt Homeostasis |
| Zdroj: | Biochimica et biophysica acta. Molecular basis of disease. 1866(10) |
| ISSN: | 1879-260X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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