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Cardiomyocyte‐Specific Deletion of Sirtuin 5 Accelerates the Development of Heart Failure Upon Dysregulating Purine Metabolism

Year: 2025

Type: article

Abstract: ABSTRACT Aim Sirtuin 5 (SIRT5), a mitochondrial NAD + ‐dependent deacylase, regulates fundamental cellular pathways, including energy substrate metabolism. The current study is designed to better elucidate the role of SIRT5 in the development of heart failure (HF). Methods Mice with cardiomyocyte‐specific deletion ( cSirt5 −/− ) or overexpression (c Sirt5 ‐Tg) of SIRT5 were generated and subjected to chronic pressure overload by transverse aortic constriction (TAC) or Sham surgery. Cardiac structure and function were assessed by echocardiography, isolated heart perfusions, and histology. MS‐based metabolomics and bulk RNA sequencing were used to explore metabolic and molecular signatures. Results c Sirt5 ‐Tg mice had similar cardiac structure and function compared to control mice, whereas c Sirt5 −/− mice displayed exacerbated cardiac dilation and dysfunction following TAC, measured both in vivo by echocardiography and ex vivo in isolated heart perfusions. Metabolomics revealed accumulation of inosine and hypoxanthine, and depletion of adenosine, adenine, AMP, and ADP in c Sirt5 −/− hearts and following TAC, indicating dysregulation of purine metabolism. RNA‐sequencing uncovered upregulation of purine‐nucleoside phosphorylase and 5′ nucleotidase, and downregulation of adenosine kinase (ADK) in c Sirt5 −/− hearts following TAC, indicating dysregulation at the interface of adenosine nucleotide salvage and purine degradation in the absence of SIRT5. Analyses of left ventricular tissue of patients with HF revealed reduced SIRT5 expression correlating with reduced ADK expression. Conclusion Loss of SIRT5 in cardiomyocytes aggravates cardiac remodeling and dysfunction in response to chronic pressure overload, involving ATP precursor depletion due to transcriptional dysregulation of cardiac purine metabolism.

Source: Acta Physiologica

DOI: 10.1111/apha.70120