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Treatment with recombinant Sirt1 rewires the cardiac lipidome and rescues diabetes-related metabolic cardiomyopathy

Abstract

Background: Metabolic cardiomyopathy (MCM), characterized by intramyocardial lipid accumulation, drives the progression to heart failure with preserved ejection fraction (HFpEF). Although evidence suggests that the mammalian silent information regulator 1 (Sirt1) orchestrates myocardial lipid metabolism, it is unknown whether its exogenous administration could avoid MCM onset. We investigated whether chronic treatment with recombinant Sirt1 (rSirt1) could halt MCM progression.

Methods: db/db mice, an established model of MCM, were supplemented with intraperitoneal rSirt1 or vehicle for 4 weeks and compared with their db/ + heterozygous littermates. At the end of treatment, cardiac function was assessed by cardiac ultrasound and left ventricular samples were collected and processed for molecular analysis. Transcriptional changes were evaluated using a custom PCR array. Lipidomic analysis was performed by mass spectrometry. H9c2 cardiomyocytes exposed to hyperglycaemia and treated with rSirt1 were used as in vitro model of MCM to investigate the ability of rSirt1 to directly target cardiomyocytes and modulate malondialdehyde levels and caspase 3 activity. Myocardial samples from diabetic and nondiabetic patients were analysed to explore Sirt1 expression levels and signaling pathways.

Results: rSirt1 treatment restored cardiac Sirt1 levels and preserved cardiac performance by improving left ventricular ejection fraction, fractional shortening and diastolic function (E/A ratio). In left ventricular samples from rSirt1-treated db/db mice, rSirt1 modulated the cardiac lipidome: medium and long-chain triacylglycerols, long-chain triacylglycerols, and triacylglycerols containing only saturated fatty acids were reduced, while those containing docosahexaenoic acid were increased. Mechanistically, several genes involved in lipid trafficking, metabolism and inflammation, such as Cd36, Acox3, Pparg, Ncoa3, and Ppara were downregulated by rSirt1 both in vitro and in vivo. In humans, reduced cardiac expression levels of Sirt1 were associated with higher intramyocardial triacylglycerols and PPARG-related genes.

Conclusions: In the db/db mouse model of MCM, chronic exogenous rSirt1 supplementation rescued cardiac function. This was associated with a modulation of the myocardial lipidome and a downregulation of genes involved in lipid metabolism, trafficking, inflammation, and PPARG signaling. These findings were confirmed in the human diabetic myocardium. Treatments that increase Sirt1 levels may represent a promising strategy to prevent myocardial lipid abnormalities and MCM development.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Clinical Chemistry
04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
Dewey Decimal Classification:610 Medicine & health
540 Chemistry
Scopus Subject Areas:Health Sciences > Internal Medicine
Health Sciences > Endocrinology, Diabetes and Metabolism
Health Sciences > Cardiology and Cardiovascular Medicine
Uncontrolled Keywords:Cardiology and Cardiovascular Medicine, Endocrinology, Diabetes and Metabolism, Cardiometabolic; Diabetes; Lipidome; Metabolic cardiomyopathy; Sirt1; Therapy
Language:English
Date:13 November 2023
Deposited On:23 Jan 2024 08:54
Last Modified:30 Dec 2024 02:54
Publisher:BioMed Central
ISSN:1475-2840
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1186/s12933-023-02057-2
PubMed ID:37957697
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  • Funder: Swiss Life Foundation
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  • Funder: Holcim Foundation
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  • Funder: Gebauer Stiftung
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  • Funder: Italian Society of Arterial Hypertension
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  • Funder: H.H. Sheikh Khalifa bin Hamad Al Thani Foundation Assistant Professorship
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  • Funder: Stiftung für wissenschaftliche Forschung
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  • Funder: Olga Mayenfisch Foundation
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  • Funder: Kurt und Senta-Hermann Stiftung
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  • Funder: EMDO Stiftung
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  • Funder: Schweizerische Diabetes-Stiftung
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  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)

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