Sestrin2 Mediates Metformin Rescued the Age-Related Cardiac Dysfunctions of Cardiorenal Syndrome Type 3.

Autor: Iglesias M; Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33620, USA., Wang H; Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33620, USA., Krause-Hauch M; Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33620, USA.; James A. Haley Veterans' Hospital, Tampa, FL 33612, USA., Ren D; Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33620, USA., Zoungrana LI; Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33620, USA., Li Z; Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33620, USA., Zhang J; Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33620, USA., Wei J; Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33620, USA., Yadav N; Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33620, USA., Patel K; Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33620, USA., Fatmi MK; Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33620, USA., Liu R; Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33620, USA., Lesnefsky EJ; Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23284, USA.; Cardiology Section, Medical Service, Richmond Department of Veterans Affairs Medical Center, Richmond, VA 23249, USA., Li J; Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33620, USA.; James A. Haley Veterans' Hospital, Tampa, FL 33612, USA.
Jazyk: angličtina
Zdroj: Cells [Cells] 2023 Mar 08; Vol. 12 (6). Date of Electronic Publication: 2023 Mar 08.
DOI: 10.3390/cells12060845
Abstrakt: Acute kidney injury (AKI) leads to acute cardiac injury and dysfunction in cardiorenal syndrome Type 3 (CRS3) through oxidative stress (OS). The stress-inducible Sestrin2 (Sesn2) protein reduces reactive oxygen species (ROS) accumulation and activates AMP-dependent protein kinase (AMPK) to regulate cellular metabolism and energetics during OS. Sesn2 levels and its protective effects decline in the aged heart. Antidiabetic drug metformin upregulates Sesn2 levels in response to ischemia-reperfusion (IR) stress. However, the role of metformin in CRS3 remains unknown. This study seeks to explore how the age-related decrease in cardiac Sesn2 levels contributes to cardiac intolerance to AKI-induced insults, and how metformin ameliorates CRS3 through Sesn2. Young (3-5 months) and aged (21-23 months) C57BL/6J wild-type mice along with cardiomyocyte-specific knockout (cSesn2 -/ - ) and their wild type of littermate (Sesn2 f/f ) C57BL/6J mice were subjected to AKI for 15 min followed by 24 h of reperfusion. Cardiac and mitochondrial functions were evaluated through echocardiograms and seahorse mitochondria respirational analysis. Renal and cardiac tissue was collected for histological analysis and immunoblotting. The results indicate that metformin could significantly rescue AKI-induced cardiac dysfunction and injury via Sesn2 through an improvement in systolic and diastolic function, fibrotic and cellular damage, and mitochondrial function in young, Sesn2 f/f , and especially aged mice. Metformin significantly increased Sesn2 expression under AKI stress in the aged left-ventricular tissue. Thus, this study suggests that Sesn2 mediates the cardioprotective effects of metformin during post-AKI.
Databáze: MEDLINE
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