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

Autor: Gong Y; The Second Department of Cardiology, The Third Hospital of Nanchang, Nanchang, Jiangxi 330009, China., Li G; Department of Pathophysiology, Qiqihar Medical University, Qiqihar 161006, China., Tao J; Department of Cardiovascular Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510000, China., Wu NN; Department of Cardiology, Fudan University Zhongshan Hospital, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Fudan University Zhongshan Hospital, Shanghai 200032, China., Kandadi MR; Medprime Health Services LLC, Paris, TX 75460, United States of America., Bi Y; Department of Cardiology, Fudan University Zhongshan Hospital, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Fudan University Zhongshan Hospital, Shanghai 200032, China., Wang S; Department of Cardiology, Fudan University Zhongshan Hospital, Shanghai 200032, China; Department of Emergency, Shanghai Tenth People's Hospital, School of Medicine Tongji University, Shanghai 200072, China; Shanghai Institute of Cardiovascular Diseases, Fudan University Zhongshan Hospital, Shanghai 200032, China., Pei Z; The Second Department of Cardiology, The Third Hospital of Nanchang, Nanchang, Jiangxi 330009, China. Electronic address: leak123@126.com., Ren J; Department of Cardiology, Fudan University Zhongshan Hospital, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Fudan University Zhongshan Hospital, Shanghai 200032, China. Electronic address: jren_aldh2@outlook.com.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2020 Oct 01; Vol. 1866 (10), pp. 165855. Date of Electronic Publication: 2020 Jun 05.
DOI: 10.1016/j.bbadis.2020.165855
Abstrakt: 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 Ca 2+ 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 Ca 2+ handling), ultrastructural disarray, apoptosis, O 2 - , 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 (Ser 757 and Ser 777 ), 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.
Competing Interests: Declaration of competing interest The authors have declared that no competing interests exist.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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