bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2024‒09‒29
seven papers selected by
Kyle McCommis, Saint Louis University
  1. Blunted Cardiac Mitophagy in Response to Metabolic Stress Contributes to HFpEF.
  2. Characterization of ferroptosis-triggered pyroptotic signaling in heart failure.
  3. The age-dependent development of abnormal cardiac metabolism in the peroxisome proliferator-activated receptor α-knockout mouse.
  4. Efficacy and safety of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with acute heart failure: a systematic review and meta-analysis.
  5. AMPK and O-GlcNAcylation: interplay in cardiac pathologies and heart failure.
  6. NPLOC4 aggravates heart failure by regulating ROS and mitochondrial function.
  7. Spaceflight-induced contractile and mitochondrial dysfunction in an automated heart-on-a-chip platform.
  1. Circ Res. 2024 Sep 27.
    Blunted Cardiac Mitophagy in Response to Metabolic Stress Contributes to HFpEF.
    Akira Yoshii, Timothy S McMillen, Yajun Wang, Bo Zhou, Hongye Chen, Durba Banerjee, Melisa Herrero, Pei Wang, Naoto Muraoka, Wang Wang, Charles E Murry, Rong Tian.
      BACKGROUND: Metabolic remodeling and mitochondrial dysfunction are hallmarks of heart failure with reduced ejection fraction. However, their role in the pathogenesis of HF with preserved ejection fraction (HFpEF) is poorly understood.METHODS: In a mouse model of HFpEF, induced by high-fat diet and Nω-nitrol-arginine methyl ester, cardiac energetics was measured by 31P NMR spectroscopy and substrate oxidation profile was assessed by 13C-isotopmer analysis. Mitochondrial functions were assessed in the heart tissue and human induced pluripotent stem cell-derived cardiomyocytes.
    RESULTS: HFpEF hearts presented a lower phosphocreatine content and a reduced phosphocreatine/ATP ratio, similar to that in heart failure with reduced ejection fraction. Decreased respiratory function and increased reactive oxygen species production were observed in mitochondria isolated from HFpEF hearts suggesting mitochondrial dysfunction. Cardiac substrate oxidation profile showed a high dependency on fatty acid oxidation in HFpEF hearts, which is the opposite of heart failure with reduced ejection fraction but similar to that in high-fat diet hearts. However, phosphocreatine/ATP ratio and mitochondrial function were sustained in the high-fat diet hearts. We found that mitophagy was activated in the high-fat diet heart but not in HFpEF hearts despite similar extent of obesity suggesting that mitochondrial quality control response was impaired in HFpEF hearts. Using a human induced pluripotent stem cell-derived cardiomyocyte mitophagy reporter, we found that fatty acid loading stimulated mitophagy, which was obliterated by inhibiting fatty acid oxidation. Enhancing fatty acid oxidation by deleting ACC2 (acetyl-CoA carboxylase 2) in the heart stimulated mitophagy and improved HFpEF phenotypes.
    CONCLUSIONS: Maladaptation to metabolic stress in HFpEF hearts impairs mitochondrial quality control and contributed to the pathogenesis, which can be improved by stimulating fatty acid oxidation.
    Keywords:  arginine methyl ester; fatty acids; heart diseases; mitophagy; ventricular dysfunction, left
    DOI:  https://doi.org/10.1161/CIRCRESAHA.123.324103
  2. Signal Transduct Target Ther. 2024 Sep 25. 9(1): 257
    Characterization of ferroptosis-triggered pyroptotic signaling in heart failure.
    Xukun Bi, Xiaotian Wu, Jiaqi Chen, Xiaoting Li, Yangjun Lin, Yingying Yu, Xuexian Fang, Xihao Cheng, Zhaoxian Cai, Tingting Jin, Shuxian Han, Meihui Wang, Peidong Han, Junxia Min, Guosheng Fu, Fudi Wang.
      Pressure overload-induced cardiac hypertrophy is a common cause of heart failure (HF), and emerging evidence suggests that excessive oxidized lipids have a detrimental effect on cardiomyocytes. However, the key regulator of lipid toxicity in cardiomyocytes during this pathological process remains unknown. Here, we used lipidomics profiling and RNA-seq analysis and found that phosphatidylethanolamines (PEs) and Acsl4 expression are significantly increased in mice with transverse aortic constriction (TAC)-induced HF compared to sham-operated mice. In addition, we found that overexpressing Acsl4 in cardiomyocytes exacerbates pressure overload‒induced cardiac dysfunction via ferroptosis. Notably, both pharmacological inhibition and genetic deletion of Acsl4 significantly reduced left ventricular chamber size and improved cardiac function in mice with TAC-induced HF. Moreover, silencing Acsl4 expression in cultured neonatal rat ventricular myocytes was sufficient to inhibit hypertrophic stimulus‒induced cell growth. Mechanistically, we found that Acsl4-dependent ferroptosis activates the pyroptotic signaling pathway, which leads to increased production of the proinflammatory cytokine IL-1β, and neutralizing IL-1β improved cardiac function in Acsl4 transgenic mice following TAC. These results indicate that ACSL4 plays an essential role in the heart during pressure overload‒induced cardiac remodeling via ferroptosis-induced pyroptotic signaling. Together, these findings provide compelling evidence that targeting the ACSL4-ferroptosis-pyroptotic signaling cascade may provide a promising therapeutic strategy for preventing heart failure.
    DOI:  https://doi.org/10.1038/s41392-024-01962-6
  3. Atherosclerosis. 2024 Sep 17. pii: S0021-9150(24)01171-7. [Epub ahead of print] 118599
    The age-dependent development of abnormal cardiac metabolism in the peroxisome proliferator-activated receptor α-knockout mouse.
    Michael S Dodd, Lucy Ambrose, Vicky Ball, Kieran Clarke, Carolyn A Carr, Damian J Tyler.
      BACKGROUND AND AIMS: Peroxisome proliferator-activated receptor α (PPARα) is crucial for regulating cardiac β-oxidation in the heart, liver, and kidney. Ageing can induce cardiac metabolic alterations, but the role of PPARα has not been extensively characterised. The aim of this research was to investigate the role of PPARα in the aged heart.METHODS: Hyperpolarized [1-13C]pyruvate was used to evaluate in vivo cardiac carbohydrate metabolism in fed and fasted young (3 months) and old (20-22 months) PPARα knockout (KO) mice versus controls. Cine MRI assessed cardiac structural and functional changes. Cardiac tissue analysis included qRT-PCR and Western blotting for Pparα, medium chain acyl-CoA dehydrenase (MCAD), uncoupling protein (UCP) 3, glucose transporter (GLUT) 4 and PDH kinase (PDK) 1,2, and 4 expression.
    RESULTS: PPARα-KO hearts from both young and old mice showed significantly reduced Pparα mRNA and a 58-59 % decrease in MCAD protein levels compared to controls. Cardiac PDH flux was similar in young control and PPARα-KO mice but 96 % higher in old PPARα-KO mice. Differences between genotypes were consistent in fed and fasted states, with reduced PDH flux when fasted. Increased PDH flux was accompanied by a 179 % rise in myocardial GLUT4 protein. No differences in PDK 1, 2, or 4 protein levels were observed between fed groups, indicating the increased PDH flux in aged PPARα-KO mice was not due to changes in PDH phosphorylation.
    CONCLUSIONS: Aged PPARα-KO mice demonstrated higher cardiac PDH flux compared to controls, facilitated by increased myocardial GLUT4 protein levels, leading to enhanced glucose uptake and glycolysis.
    Keywords:  Ageing; Cardiac metabolism; Hyperpolarized 13C MRS; PPARalpha
    DOI:  https://doi.org/10.1016/j.atherosclerosis.2024.118599
  4. Front Cardiovasc Med. 2024 ;11 1388337
    Efficacy and safety of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with acute heart failure: a systematic review and meta-analysis.
    Jingjin Hou, Li Ren, Qingbin Hou, Xiaodong Jia, Zhu Mei, Jiaxin Xu, Zheming Yang, Yiming Li, Chenghui Yan.
      Background: The effectiveness and safety of a novel class of hypoglycemic medications known as sodium-glucose cotransporter 2 (SGLT2) inhibitors have not been completely established in relation to acute heart failure (AHF). Consequently, we sought to compare the prognostic and safety outcomes of patients administered SGLT2 inhibitors for the treatment of AHF.Methods: An extensive search of the Web of Science, PubMed, and EMBASE was conducted for randomized controlled trials and observational studies that have evaluated the use of SGLT2 inhibitors in AHF from the inception of these drugs to the present. We compiled data related to cardiovascular safety and prognosis. Aggregated risk ratios (RR), mean differences (MD), or standardized mean differences (SMD) were generated for all outcomes, with 95% confidence intervals (CIs), to evaluate the predictive significance of SGLT2 inhibitors in patients with AHF.
    Results: We identified 4,053 patients from 13 studies. Patients experienced a substantial reduction in all-cause mortality (RR = 0.82, 95% CI: 0.70-0.96, P = 0.01), readmission rates (RR = 0.85, 95% CI: 0.74-0.98, P = 0.02), the number of heart failure exacerbation events (RR = 0.69, 95% CI: 0.50-0.95, P = 0.02), and the number of rehospitalization events due to heart failure (RR = 0.71, 95% CI: 0.58-0.86, P < 0.05) in the SGLT2 inhibitors-treatment group compared to a placebo or standard care (control group). SGLT2 inhibitors improved patient quality of life (SMD = -0.24, 95% CI: -0.40 to -0.09, P = 0.002). SGLT2 inhibitors were associated with enhanced diuresis in patients with AHF (MD = 2.83, 95% CI: 1.36-4.29, P < 0.05). Overall, treatment with SGLT2 inhibitors significantly reduced the level of serum NT-proBNP (MD = -497.62, 95% CI: -762.02 to -233.21, P < 0.05) and did not increase the incidence of adverse events (RR = 0.91, 95% CI: 0.82-1.01, P = 0.06).
    Conclusions: This meta-analysis suggests that treatment with SGLT2 inhibitors is associated with a better prognosis in patients with AHF than in patients not treated with SGLT2 inhibitors. It is safe and effective to initiate SGLT2 inhibitors in patients with AHF.
    Systematic Review Registration: https://www.doi.org/10.37766/inplasy2024.9.0015, identifier (INPLASY202490015).
    Keywords:  SGLT2 inhibitors; acute heart failure; adverse events; all-cause mortality; quality of life; renal function
    DOI:  https://doi.org/10.3389/fcvm.2024.1388337
  5. Essays Biochem. 2024 Sep 25. pii: EBC20240003. [Epub ahead of print]
    AMPK and O-GlcNAcylation: interplay in cardiac pathologies and heart failure.
    Ettore Vanni, Christophe Beauloye, Sandrine Horman, Luc Bertrand.
      Heart failure (HF) represents a multifaceted clinical syndrome characterized by the heart's inability to pump blood efficiently to meet the body's metabolic demands. Despite advances in medical management, HF remains a major cause of morbidity and mortality worldwide. In recent years, considerable attention has been directed toward understanding the molecular mechanisms underlying HF pathogenesis, with a particular focus on the role of AMP-activated protein kinase (AMPK) and protein O-GlcNAcylation. This review comprehensively examines the current understanding of AMPK and O-GlcNAcylation signalling pathways in HF, emphasizing their interplay and dysregulation. We delve into the intricate molecular mechanisms by which AMPK and O-GlcNAcylation contribute to cardiac energetics, metabolism, and remodelling, highlighting recent preclinical and clinical studies that have explored novel therapeutic interventions targeting these pathways.
    Keywords:  AMPK; O-GlcNAc; heart failure
    DOI:  https://doi.org/10.1042/EBC20240003
  6. Int Immunopharmacol. 2024 Sep 26. pii: S1567-5769(24)01721-1. [Epub ahead of print]142(Pt B): 113199
    NPLOC4 aggravates heart failure by regulating ROS and mitochondrial function.
    Kaidi Ren, Yi Luan, Yuanyuan Sun, Siyuan Huang, Shuwei Zhang, Yang Yang, Yage Jin, Xing Chen.
      Heart failure (HF) is a leading cause of morbidity and mortality worldwide, necessitating the discovery of new therapeutic targets. NPLOC4 is known as an endoplasmic reticulum protein involved in protein degradation and cellular stress responses. Herein, NPLOC4 was investigated for its role in HF using a transverse aortic constriction (TAC) mouse model and an Angiotensin II (Ang II)-induced H9c2 cardiomyocyte model. Transcriptomic analysis revealed NPLOC4 upregulation in HF. NPLOC4 knockdown in the TAC model inhibited HF progression, as evidenced by reduced cardiac hypertrophy and fibrosis. Subsequent knockdown experiments showed the relievement in heart failure phenotypes, reduced reactive oxygen species (ROS) levels and enhanced mitochondrial function caused by NPLOC4 depletion in Ang II-induced H9c2 cells. STRING analysis predicted ERO1α as a potential NPLOC4 interactor, with further studies identifying that NPLOC4 knockdown increases ERO1α expression and disrupts mitochondria-associated membranes (MAMs). Additionally, NPLOC4 knockdown modulated the β-catenin/GSK3β pathway, enhancing mitochondrial dynamics and mitophagy. These findings suggest NPLOC4 as a promising therapeutic target for HF.
    Keywords:  ERO1α; Heart failure; Mitochondrial function; NPLOC4; β-catenin/GSK3β pathway
    DOI:  https://doi.org/10.1016/j.intimp.2024.113199
  7. Proc Natl Acad Sci U S A. 2024 Oct;121(40): e2404644121
    Spaceflight-induced contractile and mitochondrial dysfunction in an automated heart-on-a-chip platform.
    Devin B Mair, Jonathan H Tsui, Ty Higashi, Paul Koenig, Zhipeng Dong, Jeffrey F Chen, Jessica U Meir, Alec S T Smith, Peter H U Lee, Eun Hyun Ahn, Stefanie Countryman, Nathan J Sniadecki, Deok-Ho Kim.
      With current plans for manned missions to Mars and beyond, the need to better understand, prevent, and counteract the harmful effects of long-duration spaceflight on the body is becoming increasingly important. In this study, an automated heart-on-a-chip platform was flown to the International Space Station on a 1-mo mission during which contractile cardiac function was monitored in real-time. Upon return to Earth, engineered human heart tissues (EHTs) were further analyzed with ultrastructural imaging and RNA sequencing to investigate the impact of prolonged microgravity on cardiomyocyte function and health. Spaceflight EHTs exhibited significantly reduced twitch forces, increased incidences of arrhythmias, and increased signs of sarcomere disruption and mitochondrial damage. Transcriptomic analyses showed an up-regulation of genes and pathways associated with metabolic disorders, heart failure, oxidative stress, and inflammation, while genes related to contractility and calcium signaling showed significant down-regulation. Finally, in silico modeling revealed a potential link between oxidative stress and mitochondrial dysfunction that corresponded with RNA sequencing results. This represents an in vitro model to faithfully reproduce the adverse effects of spaceflight on three-dimensional (3D)-engineered heart tissue.
    Keywords:  heart-on-a-chip; microgravity; mitochondrial dysfunction; oxidative stress; spaceflight
    DOI:  https://doi.org/10.1073/pnas.2404644121
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