bims-hafaim 2025-01-19 papers

Issue of 2025–01–19
seven papers selected by
Kyle McCommis, Saint Louis University

bioRxiv. 2024 Dec 30. pii: 2024.12.29.630689. [Epub ahead of print]

Catestatin improves heart metabolic flexibility by promoting mitochondrial structure and function.

Venkat R Chirasani, Satadeepa Kal, Nilima Biswas, Sumana Mahata, Kechun Tang, Teresa Pasqua, Ennio Avolio, Suborno Jati, Gautam Bandyopadhyay, Brian P Head, Hemal H Patel, Geert van den Bogaart, Debashis Sahoo, Sanjib Senapati, Sushil K Mahata.

Hypertension, a major cause of cardiomyopathy, is one of the most critical risk factors for heart failure and mortality worldwide. Loss of metabolic flexibility of cardiomyocytes is one of the major causes of heart failure. Although Catestatin (CST) treatment is known to be both hypotensive and cardioprotective, its effect on cardiac metabolism is unknown. In this study, we undertook a transcriptomic approach to identify differentially expressed genes that were filtered using Boolean implication relationships to develop a model of gene regulation in saline or CST-supplemented CST knockout (CST-KO) mice. The analysis revealed a set of gene signatures (fibroblast, cardiomyocyte, and macrophage) rescued after CST supplemented CST-KO mice compared to wild-type. Furthermore, we independently validated these gene signature models using publicly available patient datasets. Since the gene signature includes genes related to glucose, fatty acid metabolism, and mitochondrial function, we assessed the glucose and fatty acid uptake after CST treatment. We found that CST treatment can restore the cardiac metabolic inflexibility in CST-KO heart due to the metabolic shift of glucose utilization to fatty acid as energy source. Binding studies after immunoprecipitation and mass spectrometry revealed CST binding with ATP synthase, supported by molecular simulation and computational modeling that predicted CST binding to α/β subunit of ATP synthase. Colocalization of CST with mitochondria and increased mitochondrial membrane potential and ATP production upon CST treatment in neonatal cardiomyocytes further exhibit CST as a key regulator of cardiac metabolism and mitochondrial function.

DOI: https://doi.org/10.1101/2024.12.29.630689

Am J Physiol Heart Circ Physiol. 2025 Jan 13.

Effect of cardiomyocyte-specific lipid phosphate phosphatase 3 overexpression on high-fat diet-induced cardiometabolic dysfunction in mice.

Anu Jose, Shanmugasundaram Pakkiriswami, Angella Mercer, Yadab Paudel, Esther Yi, Jeffy Fernando, Thomas Pulinilkunnil, Petra Kienesberger.

Lipid phosphate phosphatase 3 (LPP3) is a membrane-bound enzyme that hydrolyzes lipid phosphates including the bioactive lipid, lysophosphatidic acid (LPA). Elevated circulating LPA production and cellular LPA signaling are implicated in obesity-induced metabolic and cardiac dysfunction. Deletion of LPP3 in the cardiomyocyte increases circulating LPA levels and causes heart failure and mitochondrial dysfunction in mice. To examine the influence of LPP3 modulation in the cardiomyocyte on obesity-induced cardiomyopathy, we generated mice with cardiomyocyte-specific LPP3 overexpression (LPP3OE mice) driven by the α myosin heavy chain promoter. Female and male control (LPP3FL) and LPP3OE mice were fed low-fat diet (LFD) or high-fat diet (HFD) for up to 22-23 weeks, followed by the analysis of glucose homeostasis, cardiac function, plasma LPA levels, and mitochondrial respiration in cardiac myofibers. On LFD, both female and male LPP3OE mice had markedly reduced plasma LPA levels and increased pyruvate-linked respiration when compared to LPP3FL mice while body weight and global insulin sensitivity were similar between genotypes. Following HFD feeding, female LPP3OE mice were protected from an increase in plasma LPA levels, excess adiposity, systemic insulin resistance, and systolic and diastolic cardiac dysfunction compared to LPP3FL mice. Female LPP3OE mice also maintained elevated cardiac pyruvate-linked mitochondrial respiration following HFD feeding while mitochondrial respiration was similar between genotypes in HFD-fed male mice. This study suggests that cardiomyocyte-specific LPP3 upregulation protects particularly female mice from HFD-induced metabolic dysfunction and cardiomyopathy.

Keywords: Lipid phosphate phosphatase 3; cardiomyopathy; insulin resistance; lysophosphatidic acid; mitochondrial function; obesity

DOI: https://doi.org/10.1152/ajpheart.00518.2024

Intensive Care Med Exp. 2025 Jan 17. 13(1): 6

A murine model of acute and prolonged abdominal sepsis, supported by intensive care, reveals time-dependent metabolic alterations in the heart.

Bart Jacobs, Inge Derese, Sarah Derde, Sarah Vander Perre, Lies Pauwels, Greet Van den Berghe, Jan Gunst, Lies Langouche.

BACKGROUND: Sepsis-induced cardiomyopathy (SICM) often occurs in the acute phase of sepsis and is associated with increased mortality due to cardiac dysfunction. The pathogenesis remains poorly understood, and no specific treatments are available. Although SICM is considered reversible, emerging evidence suggests potential long-term sequelae. We hypothesized that metabolic and inflammatory cardiac changes, previously observed in acute sepsis as potential drivers of SICM, partially persist in prolonged sepsis.
METHODS: In 24-week-old C57BL/6J mice, sepsis was induced by cecal ligation and puncture, followed by intravenous fluid resuscitation, subcutaneous analgesics and antibiotics, and, in the prolonged phase, by parenteral nutrition. Mice were killed after 5 days of sepsis (prolonged sepsis, n = 15). For comparison, we included acutely septic mice killed at 30 h (acute sepsis, n = 15) and healthy controls animals (HC, n = 15). Cardiac tissue was collected for assessment of inflammatory and metabolic markers through gene expression, metabolomic analysis and histological assessment.
RESULTS: In prolonged sepsis, cardiac expression of IL-1β and IL-6 and macrophage infiltration remained upregulated (p ≤ 0.05). In contrast, tissue levels of Krebs cycle intermediates and adenosine phosphates were normal, whereas NADPH levels were low in prolonged sepsis (p ≤ 0.05). Gene expression of fatty acid transporters and of the glucose transporter Slc2a1 was upregulated in prolonged sepsis (p ≤ 0.01). Lipid staining and glycogen content were elevated in prolonged sepsis together with increased gene expression of enzymes responsible for lipogenesis and glycogen synthesis (p ≤ 0.05). Intermediate glycolytic metabolites (hexose-phosphates, GADP, DHAP) were elevated (p ≤ 0.05), but gene expression of several enzymes for glycolysis and mitochondrial oxidation of pyruvate, fatty-acyl-CoA and ketone bodies to acetyl-CoA were suppressed in prolonged sepsis (p ≤ 0.05). Key metabolic transcription factors PPARα and PGC-1α were downregulated in acute, but upregulated in prolonged, sepsis (p ≤ 0.05 for both). Ketone body concentrations were normal but ketolytic enzymes remained suppressed (p ≤ 0.05). Amino acid metabolism showed mild, mixed changes.
CONCLUSIONS: Our results suggest myocardial lipid and glycogen accumulation and suppressed mitochondrial oxidation, with a functionally intact Krebs cycle, in the prolonged phase of sepsis, together with ongoing myocardial inflammation. Whether these alterations have functional consequences and predispose to long-term sequelae of SICM needs further research.

Keywords: Heart; Inflammation; Metabolism; Mitochondrial dysfunction; Mitochondrial oxidation; Sepsis; Sepsis-induced cardiomyopathy

DOI: https://doi.org/10.1186/s40635-025-00715-1

J Mol Cell Cardiol Plus. 2025 Mar;11 100273

An optimized plasmalogen modulating dietary supplement provides greater protection in a male than female mouse model of dilated cardiomyopathy.

Teleah G Belkin, Emma I Masterman, Gunes S Yildiz, Helen Kiriazis, Natalie A Mellett, Jonathon Cross, Kyah Grigolon, Akshima Dogra, Daniel Donner, Roger Chooi, Amy Liang, Andrew R Kompa, Junichi Sadoshima, Amanda J Edgley, David W Greening, Peter J Meikle, Yow Keat Tham, Julie R McMullen.

We previously reported that plasmalogens, a class of phospholipids, were decreased in a setting of dilated cardiomyopathy (DCM). Plasmalogen levels can be modulated via a dietary supplement called alkylglycerols (AG) which has demonstrated benefits in some disease settings. However, its therapeutic potential in DCM remained unknown. To determine whether an optimized AG supplement could restore plasmalogen levels and attenuate cardiac dysfunction/pathology, we placed a cardiac-specific transgenic DCM mouse model of both sexes on chow +/-1.5 % AG supplementation at ∼10 weeks of age for 16 weeks. Cardiac function was assessed by echocardiography, tissues were collected for histological and molecular analyses including lipidomics and proteomics via liquid chromatography-mass spectrometry. AG supplementation increased total plasmalogens in DCM hearts and attenuated lung congestion of both sexes, but only prevented cardiac dysfunction in males. This was associated with attenuated cardiac and renal enlargement, a more favorable pro-cardiac gene expression profile, and a trend for lower cardiac fibrosis. By lipidomics, specific d18:1 ceramide species associated with cardiac pathology were lower in the DCM hearts from mice on the AG diet, and tetralinoleoyl cardiolipins, a lipid crucial for mitochondrial function was restored with AG supplementation. Proteomic analysis of hearts from male DCM mice receiving AG supplementation revealed enrichment in mitochondrial protein network, as well as upregulation of extracellular matrix binding proteins including agrin, a protein associated with cardiac regeneration. In summary, AG supplementation restored plasmalogens in DCM hearts but showed greater therapeutic potential in males than females.

Keywords: Alkylglycerols (AG); Dilated cardiomyopathy (DCM); Heart failure; Lipidomics; Plasmalogens

DOI: https://doi.org/10.1016/j.jmccpl.2024.100273

J Mol Cell Cardiol Plus. 2023 Jun;4 100036

Mechano-energetic uncoupling in hypertrophic cardiomyopathy: Pathophysiological mechanisms and therapeutic opportunities.

Vasco Sequeira, Mark T Waddingham, Hirotsugu Tsuchimochi, Christoph Maack, James T Pearson.

Hypertrophic cardiomyopathy (HCM) is a frequent inherited form of heart failure. The underlying cause of HCM is generally attributed to mutations in genes that encode for sarcomeric proteins, but the pathogenesis of the disease is also influenced by non-genetic factors, which can contribute to diastolic dysfunction and hypertrophic remodeling. Central to the pathogenesis of HCM is hypercontractility, a state that is an antecedent to several key derangements, including increased mitochondrial workload and oxidative stress. As a result, energy depletion and mechano-energetic uncoupling drive cardiac growth through signaling pathways such as ERK and/or potentially AMPK downregulation. Metabolic remodeling also occurs in HCM, characterized by decreased fatty acid oxidation and increased glucose uptake. In some instances, ketones may also feed the heart with energy and act as signaling molecules to reduce oxidative stress and hypertrophic signaling. In addition, arrhythmias are frequently triggered in HCM, resulting from the high Ca2+-buffering of the myofilaments and changes in the ATP/ADP ratio. Understanding the mechanisms driving the progression of HCM is critical to the development of effective therapeutic strategies. This paper presents evidence from both experimental and clinical studies that support the role of hypercontractility and cellular energy alterations in the progression of HCM towards heart failure and sudden cardiac death.

Keywords: Arrhythmias; Diastolic dysfunction; Genetic and non-genetic factors; Hypercontractility; Hypertrophic cardiomyopathy; Mechano-energetic mismatch; Oxidative stress; Septum hypertrophy

DOI: https://doi.org/10.1016/j.jmccpl.2023.100036

Open Life Sci. 2024 ;19(1): 20220974

Disruption of BCAA degradation is a critical characteristic of diabetic cardiomyopathy revealed by integrated transcriptome and metabolome analysis.

Yanxia Wu, Wanxiang Jiang, Junlong Wang, Guoqing Xie, Yan Sun, Jinliang Yang.

In this study, we integrated transcriptomic and metabolomic analyses to achieve a comprehensive understanding of the underlying mechanisms of diabetic cardiomyopathy (DCM) in a diabetic rat model. Functional and molecular characterizations revealed significant cardiac injury, dysfunction, and ventricular remodeling in DCM. A thorough analysis of global changes in genes and metabolites showed that amino acid metabolism, especially the breakdown of branched-chain amino acids (BCAAs) such as valine, leucine, and isoleucine, is highly dysregulated. Furthermore, the study identified the transcription factor Gata3 as a predicted negative regulator of the gene encoding the key enzyme for BCAA degradation. These findings suggest that the disruption of BCAA degradation is a critical characteristic of diabetic myocardial damage and indicate a potential role for Gata3 in the dysregulation of BCAA metabolism in the context of DCM.

Keywords: amino acid metabolism; branched-chain amino acids; diabetic cardiomyopathy; multi-omics

DOI: https://doi.org/10.1515/biol-2022-0974

JACC Adv. 2025 Jan;4(1): 101465

Dietary Interventions in Heart Failure With Preserved Ejection Fraction: A Scoping Review.

Hayley E Billingsley, Salvatore Carbone, Elissa Driggin, Dalane W Kitzman, Scott L Hummel.

Patients with heart failure with preserved ejection fraction (HFpEF) are burdened by multiple diet-sensitive comorbidities, including obesity and malnutrition. Despite this, a low percentage of patients with HFpEF have been enrolled in dietary intervention trials in heart failure and few dietary interventions have been conducted in HFpEF exclusively. This scoping review will examine available evidence regarding dietary interventions in patients with HFpEF, highlight existing gaps in knowledge, and discuss emerging dietary therapies in this population.

Keywords: dietary patterns; dietary supplements; heart failure with preserved ejection fraction; malnutrition; sodium restriction; weight loss

DOI: https://doi.org/10.1016/j.jacadv.2024.101465