bims-hafaim 2025-04-06 papers

Issue of 2025–04–06
six papers selected by
Kyle McCommis, Saint Louis University

bioRxiv. 2025 Mar 19. pii: 2025.03.18.643760. [Epub ahead of print]

Ketone Catabolism is Essential for Maintaining Normal Heart Function During Aging.

Mariko Aoyagi Keller, Michinari Nakamura.

The heart utilizes various nutrient sources for energy production, primarily favoring fatty acid oxidation. While ketones can be fuel substrates, ketolysis has been shown to be dispensable for heart development and function in mice. However, the long-term consequences of ketolysis downregulation in the heart remain unknown. Here we demonstrate that ketone catabolism is essential for preserving cardiac function during aging. The cardiac expression of succinyl-CoA:3-ketoacid CoA transferase (SCOT), a rate-limiting enzyme in ketolysis, decreases with aging in female mice. SCOT cardiomyocyte-specific knockout (cKO) mice exhibit normal heart function at 10 weeks of age but progressively develop cardiac dysfunction and remodeling as they age, without overt hypertrophy in both sexes. Notably, ketone supplementation via a ketogenic diet partially rescues contractile dysfunction in SCOT cKO mice, suggesting ketone oxidation-independent mechanisms contribute to the development of cardiomyopathy caused by SCOT downregulation. These findings indicate that ketone catabolism is crucial for maintaining heart function during aging, and that ketones confer cardioprotection independently of ketone oxidation.

DOI: https://doi.org/10.1101/2025.03.18.643760

Biomark Res. 2025 Mar 29. 13(1): 53

Deubiquitinase OTUD7B stabilizes HNF4α to alleviate pressure overload-induced cardiac hypertrophy by regulating fatty acid oxidation and inhibiting ferroptosis.

Rujie Zheng, Wenjuan Song, Che Wang, Xiaoyu Du, Chunlei Liu, Xiaotong Sun, Chengzhi Lu.

BACKGROUND: Cardiac hypertrophy, a leading cause of heart failure, threatens global public health. Deubiquitinating enzymes (DUBs) are critical in cardiac pathophysiology by regulating protein stability, function, and degradation. Here, we investigated the role and regulating mechanism of ovarian tumor domain-containing 7B (OTUD7B) in cardiac hypertrophy by modulating fatty acid metabolism.
METHODS: Mice subjected to transverse aortic constriction (TAC) and cardiomyocytes treated with phenylephrine (PE) were used to explore the role of OTUD7B in myocardial hypertrophy. The potential molecular mechanisms underlying OTUD7B's regulation of cardiac hypertrophy were explored through transcriptome analysis and further validated in cardiomyocytes.
RESULTS: Reduced OTUD7B expression was observed in hypertrophic hearts following TAC surgery. Cardiac-specific OTUD7B deficiency exacerbated, while OTUD7B overexpression mitigated, pressure overload-induced hypertrophy and cardiac dysfunction both in vivo and in vitro. OTUD7B knockdown resulted in ferroptosis, as evidenced by decreased mitochondrial cristae, increased Fe2+ ion content, lipid peroxide accumulation, while OTUD7B overexpression inhibited ferroptosis. Mechanistically, transcriptomic analysis identified OTUD7B plays a role in the regulation of fatty acid metabolism and pathological cardiac hypertrophy. OTUD7B was found to directly bind to HNF4α, a transcription factor regulating fatty acid oxidation-related genes. Further, OTUD7B exerted deubiquitination activity to stabilize the HNF4α protein by removing K48-linked ubiquitin chains, thereby preventing its degradation via the proteasomal pathway and linking the HNF4α degradation and ferroptosis. Finally, ferroptosis inhibitors, ferrostatin-1, alleviated OTUD7B inhibition-induced ferroptosis, fatty acid metabolism suppression, and myocardial hypertrophy.
CONCLUSIONS: We confirmed that OTUD7B is involved in the regulation of ferroptosis in pressure overload-induced cardiac hypertrophy and highlighted that OTUD7B alleviates cardiac hypertrophy by regulating ferroptosis and fatty acid oxidation through deubiquitination and stabilization of HNF4α.

Keywords: Cardiac hypertrophy; Deubiquitinating enzyme; Fatty acid oxidation; Ferroptosis

DOI: https://doi.org/10.1186/s40364-025-00766-2

Front Pharmacol. 2025 ;16 1526494

The role of Perilipin 5 in pathological myocardial remodeling.

Danzeng Dunzhu, Gao Han, Qin Shanshan, Shangshi Li, Jiali Yang, Jian He, Siyu Gou, Gang Dong, Chunrong Jiang, Jun Hou.

Pathological cardiac remodeling (REM), caused by various pathological factors and characterized by changes in cardiac structure and geometry, is strongly associated with heart failure (HF). It damages cardiac tissue, alters energy metabolism, increases oxidative stress, and cause matrix metalloproteinase activation, cardiomyocyte hypertrophy, and interstitial fibrosis, leading to HF. REM determines the outcome of cardiovascular disease. Current treatments have limitations. REM is associated with cardiac energetic remodeling, and modulation of metabolic substrates may slow down the disease. Perilipin 5 (Plin5), positioned as a structural protein located on the surface of lipid droplets (LDs), is abundant in tissues and cells that rely on mitochondrial β-oxidation for energy production. It is the most recently identified member of the perilipin protein (PAT) family, with a notable enrichment in the cardiac muscle. Emerging evidence highlights the critical role of intracellular LD in the regulation of energy metabolism, with metabolic disruptions of LD being directly correlated with the incidence of metabolic disease. As a key barrier to LD, Plin5 is instrumental in controlling the catabolism of LD and regulating the metabolism and transport of fatty acids (FAs). As a protectant against excessive β-oxidation of free fatty acids (FFAs), Plin5 acts to isolate and neutralize overly oxidized fatty acids, thereby shielding the heart from myocardial remodeling instigated by a variety of etiological factors. This protective mechanism helps to ameliorate the progression of persistent and detrimental myocardial remodeling, which can otherwise lead to the development of severe heart failure. This systematic review attempts to delineate the metabolic disorders associated with pathological cardiac remodeling, focusing on the properties and regulatory mechanisms of Plin5. By synthesising current literature, it investigates the pivotal role of Plin5 in modulating the distinctive attributes, initiating factors, and molecular signaling networks underpinning pathological cardiac remodeling.

Keywords: Perilipin 5; energy metabolism; fatty acids; metabolic disorder; myocardial remodel

DOI: https://doi.org/10.3389/fphar.2025.1526494

Circulation. 2025 Apr 01.

Lymphatic Endothelial Branched-Chain Amino Acid Catabolic Defects Undermine Cardiac Lymphatic Integrity and Drive HFpEF.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, but effective treatments are lacking. Cardiac lymphatics play a crucial role in maintaining heart health by draining fluids and immune cells. However, their involvement in HFpEF remains largely unexplored.
METHODS: We examined cardiac lymphatic alterations in mice with HFpEF with comorbid obesity and hypertension, and in heart tissues from patients with HFpEF. Using genetically engineered mouse models and various cellular and molecular techniques, we investigated the role of cardiac lymphatics in HFpEF and the underlying mechanisms.
RESULTS: In mice with HFpEF, cardiac lymphatics displayed substantial structural and functional anomalies, including decreased lymphatic endothelial cell (LEC) density, vessel fragmentation, reduced branch connections, and impaired capacity to drain fluids and immune cells. LEC numbers and marker expression levels were also decreased in heart tissues from patients with HFpEF. Stimulating lymphangiogenesis with an adeno-associated virus expressing an engineered variant of vascular endothelial growth factor C (VEGFCC156S) that selectively activates vascular endothelial growth factor receptor 3 (VEGFR3) in LECs restored cardiac lymphatic integrity and substantially alleviated HFpEF. Through discovery-driven approaches, defective branched-chain amino acid (BCAA) catabolism was identified as a predominant metabolic signature in HFpEF cardiac LECs. Overexpression of branched-chain ketoacid dehydrogenase kinase (encoded by the Bckdk gene), which inactivates branched-chain ketoacid dehydrogenase (the rate-limiting enzyme in BCAA catabolism), resulted in spontaneous lymphangiogenic defects in LECs. In mice, inducible Bckdk gene deletion in LECs to enhance their BCAA catabolism preserved cardiac lymphatic integrity and protected against HFpEF. BCAA catabolic defects caused ligand-independent phosphorylation of VEGFR3 in the cytoplasm by Src kinase, leading to lysosomal degradation of VEGFR3 instead of its trafficking to the cell membrane. Reduced VEGFR3 availability on the cell surface impeded downstream Akt (protein kinase B) activation, hindered glucose uptake and utilization, and inhibited lymphangiogenesis in LECs with BCAA catabolic defects.
CONCLUSIONS: Our study provides evidence that cardiac lymphatic disruption, driven by impaired BCAA catabolism in LECs, is a key factor contributing to HFpEF. These findings unravel the crucial role of BCAA catabolism in modulating lymphatic biology, and suggest that preserving cardiac lymphatic integrity may present a novel therapeutic strategy for HFpEF.

Keywords: amino acids, branched-chain; endothelial cells; heart failure; lymphangiogenesis; vascular endothelial growth factor receptor-3

DOI: https://doi.org/10.1161/CIRCULATIONAHA.124.071741

J Cell Mol Med. 2025 Apr;29(7): e70514

Mib2 Regulates Lipid Metabolism in Heart Failure With Preserved Ejection Fraction via the Runx2-Hmgcs2 Axis.

Zhulan Cai, Shunyao Xu, Xiaohua Xiao, Chen Liu, Lingyun Zu.

Obesity and the mismanagement of lipids significantly contribute to the development of heart failure with preserved ejection fraction (HFpEF). However, the underlying molecular mechanisms that regulate the metabolic changes and disruptions in lipid balance within HFpEF remain to be fully understood. Transcriptome data for HFpEF were sourced from the National Center for Biotechnology Information (NCBI) database. A mouse model for HFpEF was developed utilising leptin-deficient (ob/ob) mice. The cardiac-specific mind bomb E3 ubiquitin protein ligase 2 (Mib2) overexpression in ob/ob mice was achieved by tail vein injection of a recombinant adeno-associated virus serotype 9 vector carrying Mib2 with a cTNT promoter (AAV9-cTNT-Mib2). In vitro, neonatal rat ventricular myocytes were exposed to fatty acid to induce lipotoxicity. The molecular mechanisms were investigated through proteomic analysis, dual luciferase reporter gene assay, and immunoprecipitation assays. GO and KEGG enrichment analyses indicated that the differentially expressed proteins (DEPs) in HFpEF were prominently enriched in pathways related to the fatty acid metabolic process. The transcriptomic and proteomic analyses of heart tissues from HFpEF mice presented a notable elevation in the expression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2). Immunoprecipitation assays revealed that mind bomb 2 (Mib2) directly interacted with runt-related transcription factor 2 (Runx2), ubiquitinating and degrading Runx2 to inhibit Hmgcs2 transcription, impeding the fatty acid metabolic process. Mice with cardiac-specific overexpression of Mib2 displayed a more pronounced progression of cardiac dysfunction and an accumulation of lipids compared to the control group. Our research uncovers a mechanism by which Mib2 modulates cardiac lipid metabolic homeostasis in HFpEF, implicating the Runx2-Hmgcs2 axis.

Keywords: Hmgcs2; Mib2; Runx2; bioinformatics analysis; fatty acid metabolism; heart failure with preserved ejection fraction

DOI: https://doi.org/10.1111/jcmm.70514

J Physiol. 2025 Apr 03.

Ketogenic diet and ketone salts differentially improve cardiometabolic complications in an HFpEF rat model.

Alexandre Gonçalves, Inês N Alves, Cláudia Mendes, Daniela Miranda, Glória Conceição, João Almeida-Coelho, Diana Martins, Isabel Miranda, Alexandre Rodrigues, Carolina Silva, Sandra Marisa Oliveira, José Sereno, Maria João Ferreira, Ulrich Dischinger, Henrique Girão, Adelino F Leite-Moreira, Vasco Sequeira, Inês Falcão-Pires.

Heart failure with preserved ejection fraction (HFpEF) remains a major health concern with limited therapeutic options. Growing evidence supports the multiple benefits of ketones in heart disease, but their impact on HFpEF remains unknown. We investigated whether increasing ketones can help to manage HFpEF. Using the ZSF1 rat model of HFpEF, 16-week-old rats were randomly assigned to one of three subgroups: (i) control diet; (ii) ketogenic diet (KD); or (iii) control diet with added exogenous ketone salts (KS) in their drinking water for 10 weeks. We found that both KD and KS ameliorated the HFpEF phenotype by improving structural echocardiographic parameters, lowering glycaemia and lipid profiles, and reducing HFpEF-related fibrosis and hypertrophy without impacting in vivo diastolic function. Nevertheless, ex vivo cardiomyocyte preparations showed improved calcium handling and myofilament relaxation, suggesting benefits at the cellular level. Interestingly, KD still proved effective, despite the potentially adverse increase in fat mass. There was decreased myofilament Ca2+ sensitivity and normalized active and passive tension in both groups, especially KS. These results suggest that providing ketone through the diet or supplements could be a valuable strategy to complement HFpEF treatment. Given the well-known challenges of implementing dietary changes, exogenous KS offer a more practical and effective option to achieve these benefits. KEY POINTS: Ketogenic diet and ketone salts effectively reversed the cardiac structural impairments associated with the ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype by ameliorating left ventricular mass. Both treatments reduced fibrosis and hypertrophy, leading to improved or, in the case of ketone salts, even reversed cardiomyocyte contractile and relaxation performance. Ketone salts also reversed HFpEF-related cardiomyocyte stiffness and prevented a reduction in the development of maximum force. Both treatments improved myofilament Ca2+ sensitivity. Both treatments also improved the metabolic profile, reducing hyperglycaemia, blood triglycerides and levels of NT-proBNP, a well-known biomarker of worsening heart failure.

Keywords: heart failure; heart failure with preserved ejection fraction; ketogenic diet; ketone salts; ketones

DOI: https://doi.org/10.1113/JP288229