bims-hafaim 2025-07-20 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2025–07–20
eleven papers selected by
Kyle McCommis, Saint Louis University

Cardiac substrate metabolism in type 2 diabetes.
Development of a Quantitative Systems Pharmacology Model to Interrogate Mitochondrial Metabolism in Heart Failure.
Adropin protects against cardiac metabolic remodeling and dysfunction in HFpEF.
AAV-mediated overexpression of CPT1B protects from cardiac hypertrophy and heart failure in a murine pressure overload model.
Computational modelling of myocardial metabolism in patients with advanced heart failure.
PHB2 protects against pressure overload-induced myocardial remodeling in mice via stabilizing TOMM40 and regulating mitochondrial morphofunctional homeostasis.
SARM1 Exacerbates Pressure Overload-Induced Cardiac Hypertrophy and Heart Failure by Enhancing NAD+ Metabolism.
Metabolite Profiles of Heart Failure, Central Hemodynamic Derangement, and Response to Heart Transplantation.
The effect of empagliflozin on cardiac function and structure in patients with heart failure with reduced ejection fraction: a systematic review and meta-analysis.
A Transient Increase in Cardiomyocyte Protein O-GlcNAcylation Enhances Susceptibility to Pressure Overload-Induced Cardiac Remodeling.
Vericiguat as a novel PPARα ligand alleviates pressure-overload-induced heart failure.

Biochem J. 2025 May 21. 482(10): 499-518

Cardiac substrate metabolism in type 2 diabetes.

Jordan S F Chan, Tanin Shafaati, John R Ussher.

  As the most metabolically demanding organ on a per gram basis, substrate metabolism in the heart is intricately linked to cardiac function. Virtually all major cardiovascular pathologies are associated with perturbations in cardiac substrate metabolism, and increasing evidence supports that these perturbations in substrate metabolism can directly contribute to cardiac dysfunction. Furthermore, type 2 diabetes (T2D) is a major risk factor for increased cardiovascular disease burden, while also being characterized by a very distinct metabolic profile in the heart. This includes increases in cardiac fatty oxidation rates and a robust reduction in cardiac glucose oxidation rates. Herein, we will describe the primary mechanisms responsible for the increase in cardiac fatty acid oxidation and decrease in cardiac glucose oxidation during T2D, while also detailing perturbations in cardiac ketone and amino acid metabolism. In addition, we will interrogate preclinical studies that have addressed whether correcting perturbations in cardiac substrate metabolism may have clinical utility against ischemic heart disease, diabetic cardiomyopathy, or heart failure associated with T2D. Lastly, we will consider the translational potential of such an approach to manage cardiovascular disease in people living with T2D.

Keywords:  cardiac substrate metabolism; diabetes; diabetic cardiomyopathy; diastolic dysfunction

DOI:  https://doi.org/10.1042/BCJ20240189
bioRxiv. 2025 Jul 11. pii: 2025.07.08.663697. [Epub ahead of print]

Development of a Quantitative Systems Pharmacology Model to Interrogate Mitochondrial Metabolism in Heart Failure.

Lyndsey F Meyer, Neda Nourabadi, Cynthia J Musante, Daniel A Beard, Anna Sher.

The metabolic hallmarks of heart failure (HF) include diminished ATP hydrolysis potential and alterations in myocardial energy substrate metabolism, such as a switch in substrate utilization away from fatty acid (FA) to carbohydrate oxidation and reduced metabolic flexibility. However, the mechanisms underlying these phenomena and their potential contributions to impaired exercise tolerance are poorly understood. We developed a comprehensive quantitative systems pharmacology (QSP) model of mitochondrial metabolism to interrogate specific pathways hypothesized to contribute to reductions in reserve cardiac power output in heart failure. The aim of this work was to understand how changes in mitochondrial function and cardiac energetics associated with heart failure may affect exercise capacity. To accomplish this task, we coupled published in silico models of oxidative phosphorylation and the tricarboxylic acid cycle with a model of β-oxidation and extended the model to incorporate an updated representation of the enzyme pyruvate dehydrogenase (PDH) to account for the role of PDH in substrate selection. We tested several hypotheses to determine how metabolic dysfunction, such as a decrease in PDH activity or altered mitochondrial volume, could lead to marked changes in energetic biomarkers, such as myocardial phosphocreatine-ATP ratio (PCr/ATP). The model predicts expected changes in fuel selection and also demonstrates PDH activity is responsible for substrate-dependent switch driven by feedback from NAD, NADH, ATP, ADP, CoASH, Acetyl-CoA and pyruvate in healthy and simulated HF conditions. Through simulations, we also found elevated malonyl-coA may contribute to lower PCr/ATP ratio during exercise conditions as observed in some HF patients.
Key Points: Exercise intolerance is a hallmark of heart failure in patients with preserved ejection fractionWe developed a quantitative systems pharmacology modeling approach with the potential to interrogate mitochondrial pathways hypothesized to contribute to exercise intoleranceThe model was developed and evaluated based on simulating in vitro experimental dataSubstrate selection is an emergent property of the model with an increase in ATP demand resulting in a relative increase in the use of carbohydrates to fuel oxidative phosphorylation, an effect driven by feedback regulation of pyruvate dehydrogenaseThe model was used to predict the potential effects of targeted perturbations to key mitochondrial pathways.

DOI: https://doi.org/10.1101/2025.07.08.663697
bioRxiv. 2025 May 08. pii: 2025.05.03.652038. [Epub ahead of print]

Adropin protects against cardiac metabolic remodeling and dysfunction in HFpEF.

Bellina A S Mushala, Michael W Stoner, Janet R Manning, Paramesha Bugga, Nisha Bhattarai, Maryam Sharifi-Sanjani, Brenda McMahon, Amber Vandevender, Steven J Mullet, Brett A Kaufman, Sruti S Shiva, Cheng Zhang, Eric Goetzman, Stephen Y Chan, Stacy L Gelhaus, Michael J Jurczak, Iain Scott.

Cardiometabolic heart failure with preserved ejection fraction (HFpEF) is a heterogenous metabolic disease, which in the heart presents as left ventricle diastolic dysfunction, ventricular stiffness, and myocardial structural remodeling. Deleterious changes in cardiac metabolism are central to HFpEF pathophysiology, and proposed treatments for the disease have focused on repairing these defects. In this study, we used a preclinical mouse model that recapitulates cardiometabolic HFpEF to elucidate the molecular mechanisms driving cardiac dysfunction, and tested whether recombinant Adropin (a liver- and brain-derived peptide hormone) could reverse observed defects. We show that long-term treatment with Adropin reversed multiple markers of HFpEF-related cardiac dysfunction (including fibrosis, diastolic dysfunction, and cardiomyocyte hypertrophy). Using untargeted metabolomics, we found that Adropin treatment restricted deleterious metabolite entry into the hexosamine biosynthesis pathway, leading to a reduction in the inhibitory O-GlcNAcylation of the cardiac fatty acid oxidation enzyme long chain acyl-CoA dehydrogenase. Our results suggest that Adropin may restore cardiac metabolic function in HFpEF, and that targeting this pathway may be a novel therapeutic avenue for this disease.

DOI: https://doi.org/10.1101/2025.05.03.652038
Basic Res Cardiol. 2025 Jul 11.

AAV-mediated overexpression of CPT1B protects from cardiac hypertrophy and heart failure in a murine pressure overload model.

Anca Kliesow Remes, Theresa Ruf, Tinatin Zurashvili, Lin Ding, Moritz Meyer-Jens, Dominic M Schwab, Susanne Hille, Andrea Matzen, Sabine Michalewski, Lucia Kilian, Prithviraj Manohar Vijaya Shetty, Marie-Christin Fuchs, Matthias Eden, Hermann-Josef Gröne, Kleopatra Rapti, Andreas Jungmann, Hendrik Milting, Hugo A Katus, Lucie Carrier, Derk Frank, Norbert Frey, Oliver J Müller.

  The transition from cardiac hypertrophy to heart failure is characterized by metabolic changes like downregulation of fatty acid metabolism in favor of increased glucose utilization. Carnitine palmitoyltransferase 1B (CPT1B) catalyzes the rate-limiting step of the carnitine shuttle and is an essential enzyme for fatty acid oxidation. Down-regulation of CPT1B activity has been associated with heart failure in patients and various experimental models, indicating an important role in metabolic remodeling. Therefore, we aimed to investigate whether CPT1B overexpression could play a therapeutic role in heart failure. Gene transfer of CPT1B using adeno-associated virus (AAV) vectors into neonatal rat cardiomyocytes significantly attenuated phenylephrine-induced hypertrophy and resulted in decreased generation of mitochondrial reactive oxygen species. In mice subjected to transverse aortic constriction, AAV-mediated cardiac overexpression of CPT1B attenuated cardiomyocyte hypertrophy, cardiac fibrosis, and systolic dysfunction in vivo. Upregulation of CPT1B expression might therefore represent a promising approach to treat or prevent heart failure.

Keywords:  Adeno-associated virus; CPT1B; Cardiac hypertrophy; Fatty acid metabolism; Heart failure; Metabolic remodeling

DOI:  https://doi.org/10.1007/s00395-025-01123-y
Eur J Heart Fail. 2025 Jul 15.

Computational modelling of myocardial metabolism in patients with advanced heart failure.

Niklas Beyhoff, Vera M Braun, Marieluise Kirchner, Lucy E M Finnigan, Christoph Knosalla, István Baczkó, Evgenij Potapov, Ulrich Kintscher, Tilman Grune, Titus Kuehne, Hermann-Georg Holzhütter, Philipp Mertins, Damian J Tyler, Hendrik Milting, Betty Raman, Oliver J Rider, Stefan Neubauer, Nikolaus Berndt.

   AIMS: Perturbations of myocardial metabolism and energy depletion are well-established hallmarks of heart failure (HF), yet methods for their systematic assessment remain limited in humans. This study aimed to determine the ability of computational modelling of patient-specific myocardial metabolism to assess individual bioenergetic phenotypes and their clinical implications in HF.
METHODS AND RESULTS: Based on proteomics-derived enzyme quantities in 136 cardiac biopsies, personalized computational models of myocardial metabolism were generated in two independent cohorts of advanced HF patients together with sex- and body mass index-matched non-failing controls. The bioenergetic impact of dynamic changes in substrate availability and myocardial workload were simulated, and the models' ability to predict the myocardial response following left ventricular assist device (LVAD) implantation was assessed. Compared to controls, HF patients had a reduced ATP production capacity (p < 0.01), although there was remarkable interindividual variance. Utilization of glucose relative to fatty acids was generally higher in HF patients, depending on substrate availability and myocardial workload. The ratio of fatty acid to glucose utilization was associated with reverse cardiac remodelling after LVAD implantation and highly predictive of an improvement in left ventricular ejection fraction ≥10% (C-index 0.94 [0.81-1.00], p < 0.01). System-level simulations identified fatty acid administration and carnitine supplementation in those with low mitochondrial carnitine content as potential pharmacological interventions to restore myocardial substrate utilization.
CONCLUSIONS: Computational modelling identified a subset of advanced HF patients with preserved myocardial metabolism despite a similar degree of systolic dysfunction. Substrate preference was associated with the myocardial response after LVAD implantation, which suggests a role for substrate manipulation as a therapeutic approach. Computational assessment of myocardial metabolism in HF may improve understanding of disease heterogeneity, individual risk stratification, and guidance of personalized clinical decision-making in the future.

Keywords:  Cardiomyopathy; Computational modelling; Heart failure; Metabolism; Precision medicine; Proteomics; Ventricular assist device

DOI:  https://doi.org/10.1002/ejhf.3746
Acta Pharmacol Sin. 2025 Jul 14.

PHB2 protects against pressure overload-induced myocardial remodeling in mice via stabilizing TOMM40 and regulating mitochondrial morphofunctional homeostasis.

Dan Li, Jia-Hao Li, Ying-Ying Guo, Ya-Jie Chen, Meng Zhang, Fei-Xue Xu, Wan-Yi Li, Qi-Zhu Tang.

  Myocardial remodeling is critical pathological processes in various cardiovascular diseases, where redox imbalance and mitochondrial bioenergetic perturbations emerge as key determinants. Prohibitin 2 (PHB2), which resides in the mitochondrial inner membrane, serves as a critical regulator of mitochondrial homeostasis. In this study we investigated the protective role of PHB2 in transverse aortic constriction (TAC)-induced cardiac remodeling with a particular focus on its ability to safeguard the heart by improving mitochondrial function and alleviating oxidative stress. We revealed that PHB2 expression was significantly decreased in the heart of TAC mice and in Ang II (1 μM)-treated cardiomyocytes. Cardiac-specific PHB2 overexpression mitigated TAC-induced cardiac remodeling, improving cardiac function and attenuating hypertrophy. Additionally, PHB2 overexpression effectively suppressed oxidative stress in the hearts of TAC mice, while improving mitochondrial morphology and the integrity of inner membrane structure. Furthermore, PHB2 overexpression restored mitochondrial function in Ang II-treated cardiomyocytes evidenced by elevated ATP levels and enhanced oxidative phosphorylation capacity. IP-MS analysis revealed that PHB2 directly interacted with Transporter of Outer Mitochondrial Membrane 40 (TOMM40) to regulate mitochondrial function. Importantly, silencing TOMM40 abolished the protective effects of PHB2. We demonstrated that PHB2 preserves TOMM40 protein levels predominantly through inhibition of ubiquitin-dependent proteasomal degradation. Collectively, we discover a new function of PHB2 in safeguarding mitochondrial morphofunctional homeostasis in response to pathological stress through facilitating TOMM40 stabilization, suggesting PHB2 as a promising therapeutic target for potential interventions in heart diseases. Schematic illustration of PHB2's potential protective mechanism against cardiac hypertrophy. PHB2 protects against pressure overload-induced cardiac hypertrophy through preserving TOMM40 protein to maintain mitochondrial energetic homeostasis.

Keywords:  Prohibitin 2; TOMM40; cardiac remodeling; mitochondria; pressure overload

DOI:  https://doi.org/10.1038/s41401-025-01613-8
FASEB J. 2025 Jul 31. 39(14): e70808

SARM1 Exacerbates Pressure Overload-Induced Cardiac Hypertrophy and Heart Failure by Enhancing NAD+ Metabolism.

Hui-Ting Shi, Guo-Jun Zhao, Si-Jia Liu, Bin-Bin Du, Li-Li Xiao, Zhen Huang, Dian-Hong Zhang, Lei-Ming Wu, Yan-Yu Lu, Qi-Guang Du, Er-Kui Wang, Yan-Zhou Zhang.

  Heart failure (HF) represents the terminal phase in the progression of numerous clinical conditions, with high mortality and significant economic impact. Nicotinamide adenine dinucleotide (NAD+) is a crucial cofactor in HF pathogenesis. Sterile alpha and TIR motifs of 1 (SARM1) is an intracellular NAD+ hydrolase that plays a well-defined role in axonal degeneration and neuronal injury, but its role in HF is unclear. Consequently, our study sought to elucidate the role of SARM1 in the context of HF. We generated in vivo and in vitro HF models using transverse aortic constriction in mice and phenylephrine stimulation of neonatal rat cardiomyocytes (NRCMs) to study the effects of Sarm1 gene deletion and SARM1 overexpression. Our findings revealed a significant increase in SARM1 expression in HF and demonstrated that SARM1 suppression could mitigate adverse cardiac remodeling and dysfunction, whereas overexpression of SARM1 had the opposite effects. Subsequent investigations indicated that SARM1 functions in reducing cardiac NAD+ levels, impairing mitochondrial bioenergetics, and exacerbating HF progression. Conversely, supplementation with nicotinamide mononucleotide (NMN) ameliorated hypertrophy in NRCMs overexpressing SARM1 following phenylephrine induction. SARM1 is a key factor in HF by reducing intracellular NAD+ levels, making it a potential target for HF therapy.

Keywords:  NAD+ metabolism; cardiac hypertrophy; heart failure; mitochondrial dysfunction; sterile alpha and TIR motif containing 1

DOI:  https://doi.org/10.1096/fj.202500486RR
J Am Heart Assoc. 2025 Jul 15. 14(14): e039248

Metabolite Profiles of Heart Failure, Central Hemodynamic Derangement, and Response to Heart Transplantation.

Carl Lejonberg, Tomasz Czuba, Anna Egerstedt, Nilanjana Ghosh, Selvi Celik, Charlotta Ljungman, Jakob Lundgren, Göran Rådegran, Olof Gidlöf, J Gustav Smith.

   BACKGROUND: Heart failure (HF) is characterized by hemodynamic derangements that are likely to mediate systemic metabolic perturbations but limited data are available. Plasma metabolite profiling provides opportunities for comprehensive investigation of such perturbations. Here, we aimed to characterize plasma profiles that associate with HF and their relationship with central hemodynamics, symptom burden, and response to restoration of cardiac function by heart transplantation.
METHODS: Untargeted metabolite profiling was conducted with mass spectrometry in 2 independent case-control samples.
RESULTS: In total, 89 of 797 studied metabolites were significantly associated with HF in both cohorts with concordant directionality. Amino acid, carbohydrate, and nucleotide metabolites were enriched for association with HF and were consistently increased in HF cases. A subset of patients with advanced HF subsequently underwent heart transplantation, after which 17 of the 89 metabolites returned significantly toward healthy control levels. These 17 metabolites represent increased catecholamine and heme metabolism, conjugated bile acids, kynurenine pathway mediators, spermidine metabolism, and allantoin, as well as tricarboxylic acid cycle and glycolysis intermediates. Most of these metabolites associated with symptom burden and at least 1 of 12 central hemodynamic parameters, primarily relating to either increased systemic or pulmonary venous congestion, lower cardiac output, or lower left ventricular stroke work.
CONCLUSIONS: We comprehensively identified metabolite profiles associated with HF and central hemodynamics that reverse by cardiac transplantation. Increased levels of most metabolites also associated with higher symptom burden. Our findings provide perspectives on the metabolic consequences of HF with potential implications for noninvasive monitoring and tailored therapy.

Keywords:  heart failure; hemodynamics; metabolomics; transplantation

DOI:  https://doi.org/10.1161/JAHA.124.039248
Postepy Kardiol Interwencyjnej. 2025 Jun;21(2): 146-154

The effect of empagliflozin on cardiac function and structure in patients with heart failure with reduced ejection fraction: a systematic review and meta-analysis.

Geli Nan, Cui Bing Yang, Zhi Kun Jia.

   Introduction: Empagliflozin was shown to improve the clinical outcomes of cardiovascular diseases; however, its effects on cardiac structure and cardiac remodeling in patients with heart failure remain controversial to some extent.
Aim: We conducted this meta-analysis to compare the effect of empagliflozin with placebo on cardiac structure and function among patients with heart failure.
Methods: PubMed, Scopus, Web of Science, and the Cochrane Library were systematically searched from inception to December 20, 2024, to identify randomized controlled trials comparing the effects of empagliflozin with placebo on cardiac structure and function in patients with heart failure. A random-effects model (DerSimonian-Laird) was employed to pool data.
Results: Four studies with 234 individuals in the empagliflozin group and 231 individuals in the placebo group were included. Compared to placebo, empagliflozin 10 (mg/day) significantly increased left ventricular ejection fraction (LVEF) (WMD 2.96%, 95% CI (0.84, 5.09), I 2 = 85.28%), decreased left ventricular (LV) end-diastolic volume (WMD -17.05 ml, 95% CI (-23.68, -10.42), I 2 = 13.88%), LV end-diastolic volume index (WMD -7.59 ml/m2, 95% CI (-10.08, -5.10), I 2 = 0.00%), LV end-systolic volume (WMD -15.59 ml, 95% CI (-25.89, -5.28), I 2 = 74.69%), LV end-systolic volume index (WMD -6.68 ml/m2, 95% CI (-7.95, -5.41), I 2 = 0.00%), and left atrial volume index (WMD -2.16 ml/m2, 95% CI (-4.21, -0.10), I 2 = 0.00%), but did not significantly change LV mass (WMD -11.66 g, 95% CI (-30.54, 7.22), I 2 = 90.02%) and LV mass index (WMD -4.01 g/m2, 95% CI (-10.94, 2.92), I 2 = 64.29%).
Conclusions: Empagliflozin can significantly improve myocardial function and prevent myocardial remodeling in patients with heart failure.

Keywords:  cardiac function; cardiac structure; empagliflozin; heart failure; left ventricular ejection fraction; left ventricular end-diastolic volume; left ventricular end-systolic volume

DOI:  https://doi.org/10.5114/aic.2025.151600
bioRxiv. 2025 Jun 07. pii: 2025.06.04.657956. [Epub ahead of print]

A Transient Increase in Cardiomyocyte Protein O-GlcNAcylation Enhances Susceptibility to Pressure Overload-Induced Cardiac Remodeling.

Samuel F Chang, Chae-Myeong Ha, Manoja K Brahma, Luke A Potter, Mahima S Reddy, Sayan Bakshi, Kerstin Preuß, Md Saimoon Rahman, Johannes K Fischer, Caitlin A Harrell, Zhihuan Sun, John C Chatham, Adam R Wende.

BACKGROUND: The observation that diabetic patients always under tight-glycemic control consistently show better cardiovascular disease outcomes compared to patients who transition to tight-glycemic control after prior conventional glycemic control lead to the concept of metabolic memory. Mechanisms such as epigenetics possibly mediate the lasting metabolic memory effects, our understanding of the underlying mechanisms remains limited. Increased cardiac protein posttranslational O-linked β-N-acetylglucosamine (O-GlcNAc) modification is implicated in cardiac remodeling observed in diabetes, and our previous work shows chronically elevated cardiomyocyte O-GlcNAc causes adverse cardiac changes. Therefore, the current study hypothesized that transiently increased cardiomyocyte O-GlcNAcylation leads to exacerbated adverse cardiac remodeling after subsequent pressure-overload.
METHODS AND RESULTS: Using our previously described inducible cardiomyocyte specific, dominant-negative O-GlcNAcase (dnOGAh) mouse and single transgenic littermate controls (Con), we induced O-GlcNAc levels for 2wk (ON), followed by a 2wk washout (OFF); mice then underwent transverse-aortic constriction (TAC) or Sham surgery. We observed the expected cardiac remodeling in TAC groups, including decreased cardiac function, and increased hypertrophy and fibrosis. Moreover, these pathologic measures were exacerbated in the ON/OFF-TAC vs. Con-TAC mice; additionally, transcriptomic analysis of LV-tissue from each experimental group showed pathways which not only supported our fibrosis, hypertrophy and functional results of exacerbated cardiac remodeling, but also, revealed potential novel molecular pathways underlying this pathologic remodeling.
CONCLUSIONS: We observed exacerbated cardiac pathology between ON/OFF-TAC vs. Con-TAC groups supporting the concept of "O-GlcNAc memory" as a component of metabolic memory. Moreover, transcriptomic analysis provides insight into potential molecular pathways underpinning this metabolic/O-GlcNAc memory such as Ccn2 /CTGF-driven fibrosis, and/or Nox4 -driven oxidative stress.
GRAPHICAL ABSTRACT:
Clinical Perspective: What is new?: We provide a novel paradigm to study phenotypic and molecular effects of specific, transiently increased cardiomyocyte O-GlcNAcylation on the heart.Our results show exacerbated adverse cardiac remodeling due to transiently increased cardiomyocyte O-GlcNAc with pressure-overload, supporting the concept of "O-GlcNAc memory" as a component of metabolic memory.Transcriptomic insights show gene expression basis for not only observed exacerbated adverse cardiac remodeling (e.g., hypertrophy, fibrosis, cardiac dysfunction), but also potential molecular pathways that could drive cardiac pathology exacerbation of O-GlcNAc memory.What are the clinical implications?: This study supports a concept of "O-GlcNAc memory", where previously increased cardiomyocyte protein O-GlcNAcylation can impact the later development of differential cardiac pathology-like the pathology seen in metabolic memory research.The potential role of O-GlcNAc in mediating metabolic memory will help focus future translational research on this modification and downstream cardiac effects in diabetes.Transcriptomic profiling of cardiac remodeling in this model provides an investigational roadmap for future molecular and functional studies to identify novel therapeutics that ameliorate heart disease induced by differential metabolic memory.

DOI: https://doi.org/10.1101/2025.06.04.657956
Toxicol Appl Pharmacol. 2025 Jul 12. pii: S0041-008X(25)00249-2. [Epub ahead of print]503 117473

Vericiguat as a novel PPARα ligand alleviates pressure-overload-induced heart failure.

Peng Zhang, Chenxin Yuan, Zhujing Zhan, Jianghua Zhou, Pan Huang, Wenhan Wang, Jinfu Qian, Peiren Shan.

  Heart failure (HF) remains a critical global health challenge with limited therapeutic options. Vericiguat, a novel soluble guanylate cyclase (sGC) stimulator, has demonstrated clinical potential in HF management. This study aimed to investigate the cardioprotective effects of vericiguat and its underlying mechanism in pressure-overload-induced HF. Using a transverse aortic constriction (TAC) mouse model, we demonstrated that vericiguat significantly improved cardiac function and attenuated myocardial hypertrophy, fibrosis, and oxidative stress. In vitro, vericiguat mitigated isoproterenol (ISO)-induced hypertrophy and oxidative stress in HL-1 cardiomyocytes. RNA sequencing and pathway enrichment analysis revealed that vericiguat exerts its protective effects by modulating metabolic pathways, particularly through the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Vericiguat upregulated PPARα expression at both mRNA and protein levels, with no significant effect on PPARβ or PPARγ. CETSA and DARTS assays confirmed a direct interaction between vericiguat and PPARα, further supported by molecular docking showing stable hydrogen bonding and hydrophobic interactions, notably with residue SER280. Pharmacological inhibition of PPARα with GW6471 abolished vericiguat's protective effects, underscoring the central role of PPARα activation. In conclusion, vericiguat alleviates pressure-overload-induced HF by directly binding to, upregulating and activating PPARα, offering a novel therapeutic approach for the treatment of HF.

Keywords:  Cardiac hypertrophy; Heart failure; Oxidative stress; PPARα; Vericiguat

DOI:  https://doi.org/10.1016/j.taap.2025.117473