bims-hafaim 2025-10-19 papers

Issue of 2025–10–19
three papers selected by
Kyle McCommis, Saint Louis University

Acta Physiol (Oxf). 2025 Nov;241(11): e70120

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

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 (cSirt5-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: cSirt5-Tg mice had similar cardiac structure and function compared to control mice, whereas cSirt5-/- 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 cSirt5-/- 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 cSirt5-/- 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.

Keywords: SIRT5; adenosine kinase; heart failure; purine metabolism; sirtuin

DOI: https://doi.org/10.1111/apha.70120

Front Cardiovasc Med. 2025 ;12 1678992

Metabolic dysregulation in the heart in obesity-associated HFpEF.

Maria Valero-Muñoz, Hannah L Cooper, Shanpeng Li, Eng Leng Saw, Richard M Wilson, Christine M Kusminski, Philipp E Scherer, Flora Sam.

Background: Obesity and hypertension are among the most prevalent comorbidities in heart failure with preserved ejection fraction (HFpEF). In addition to its relationship with hypertension in HFpEF, obesity is also strongly associated with insulin resistance (IR) and type 2 diabetes (T2D). However, the exact cardiac effects underlying this relationship are unknown. We sought to differentiate the cardiac phenotype associated with increased adiposity in the presence or absence of IR in obese HFpEF. We utilized adipose tissue-specific MitoNEET transgenic mice, which develop chronic, metabolically healthy adipose tissue expansion (obese non-insulin resistant, OB-NIR), and compared them with their wild-type, insulin-resistant littermates (OB-IR).
Methods: OB-NIR MitoNEET and OB-IR wildtype mice were fed a high-fat diet for 16 weeks, at which time HFpEF was induced via uninephrectomy, d-aldosterone infusion, and 1.0% sodium chloride drinking water for 4 additional weeks while maintained on the same diet.
Results: OB-NIR HFpEF mice exhibited reduced cardiac fibrosis without changes in hypertrophy. This reduction was accompanied by increased cardiac expression of SIRT3. Upregulation of several downstream mitochondrial targets of SIRT3 was also observed. These included mitochondrial fission protein 1 (Fis1), a critical regulator of mitochondrial dynamics, and the antioxidant enzyme heme oxygenase-1 (Hmox1). In contrast, levels of hydroxy-3-methylglutaryl coenzyme A (CoA) synthase 2 (HMGCS2) were decreased, while both 3-hydroxybutyrate dehydrogenase 1 (Bdh1) and succinyl-CoA:3-ketoacid CoA transferase (Oxct1) were elevated. Furthermore, genes involved in the electron transport chain, such as ubiquinol-cytochrome C reductase hinge protein (Uqcrh, Complex III) and mitochondrially encoded cytochrome c oxidase I (Mt-Co1, Complex IV), were upregulated.
Discussion: Distinct alterations in cardiac mitochondrial function were observed depending on the presence or absence of IR in obese HFpEF mice. These findings suggest that SIRT3 may play a central role in mediating mitochondrial adaptations in the heart and could represent a promising therapeutic target in HFpEF.

Keywords: HFPEF; SIRT3; insulin resistance; mitochondria metabolism; obesity

DOI: https://doi.org/10.3389/fcvm.2025.1678992

Front Pharmacol. 2025 ;16 1676988

Mitochondrial dysfunction as a therapeutic nexus in HFpEF: therapeutic target and pharmacological advances.

Tian Yue, Dezhi Zheng, Jian He, Shiqiang Xiong, Junbo Xu, Jun Hou.

Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for approximately 50% of all HF cases, and its incidence continues to rise with population aging and the surge in metabolic diseases. Unlike heart failure with reduced ejection fraction (HFrEF), HFpEF lacks effective therapeutic regimens to improve prognosis, with a 5-year mortality rate as high as 50%. Mitochondrial dysfunction, as a key link connecting metabolic disorders and abnormal myocardial systolic and diastolic function, has become a critical mechanism in the pathophysiology of HFpEF and a potential therapeutic target. This review systematically elaborates on the molecular mechanisms in HFpEF, such as mitochondrial energy metabolism disorders, dynamic imbalance, oxidative stress injury, and calcium signal dysregulation, comprehensively reviews the evidence for the effects of marketed drugs and drugs in clinical trials that improve mitochondrial function, and simultaneously explores emerging therapeutic strategies targeting mitochondria. This review aims to provide a theoretical reference for mechanistic research and drug development of HFpEF and promote the application of precision therapy targeting mitochondrial dysfunction in clinical practice.

Keywords: HFpEF; drug development; mitochondrial dysfunction; mitochondrial targeting; therapeutic strategies

DOI: https://doi.org/10.3389/fphar.2025.1676988