bims-carmet Biomed News
on Cardiac metabolism
Issue of 2021–12–19
ten papers selected by
Mikky Atsér, University of British Columbia
  1. Regulating Polyamine Metabolism by miRNAs in Diabetic Cardiomyopathy.
  2. Cancer-A Major Cardiac Comorbidity With Implications on Cardiovascular Metabolism.
  3. Fatty acid metabolism and acyl-CoA synthetases in the liver-gut axis.
  4. Mitochondrial Transfer in Cardiovascular Disease: From Mechanisms to Therapeutic Implications.
  5. In vivo identification and validation of novel potential predictors for human cardiovascular diseases.
  6. Protein phosphatase 2A in the healthy and failing heart: New insights and therapeutic opportunities.
  7. An update on triglyceride-rich lipoproteins and their remnants in atherosclerotic cardiovascular disease.
  8. New Insights Into the Role of Mitochondria Quality Control in Ischemic Heart Disease.
  9. Very long-chain saturated fatty acids and diabetes and cardiovascular disease.
  10. Hallmarks of exercised heart.
  1. Curr Diab Rep. 2021 Dec 13. 21(12): 52
    Regulating Polyamine Metabolism by miRNAs in Diabetic Cardiomyopathy.
    Tyler N Kambis, Hadassha M N Tofilau, Flobater I Gawargi, Surabhi Chandra, Paras K Mishra.
       PURPOSE OF REVIEW: Insulin is at the heart of diabetes mellitus (DM). DM alters cardiac metabolism causing cardiomyopathy, ultimately leading to heart failure. Polyamines, organic compounds synthesized by cardiomyocytes, have an insulin-like activity and effect on glucose metabolism, making them metabolites of interest in the DM heart. This review sheds light on the disrupted microRNA network in the DM heart in relation to developing novel therapeutics targeting polyamine biosynthesis to prevent/mitigate diabetic cardiomyopathy.
    RECENT FINDINGS: Polyamines prevent DM-induced upregulation of glucose and ketone body levels similar to insulin. Polyamines also enhance mitochondrial respiration and thereby regulate all major metabolic pathways. Non-coding microRNAs regulate a majority of the biological pathways in our body by modulating gene expression via mRNA degradation or translational repression. However, the role of miRNA in polyamine biosynthesis in the DM heart remains unclear. This review discusses the regulation of polyamine synthesis and metabolism, and its impact on cardiac metabolism and circulating levels of glucose, insulin, and ketone bodies. We provide insights on potential roles of polyamines in diabetic cardiomyopathy and putative miRNAs that could regulate polyamine biosynthesis in the DM heart. Future studies will unravel the regulatory roles these miRNAs play in polyamine biosynthesis and will open new doors in the prevention/treatment of adverse cardiac remodeling in diabetic cardiomyopathy.
    Keywords:  Diabetes; Heart; Insulin; Ketone body; Methionine cycle; T1DM; T2DM; Urea cycle
    DOI:  https://doi.org/10.1007/s11892-021-01429-w
  2. Front Physiol. 2021 ;12 729713
    Cancer-A Major Cardiac Comorbidity With Implications on Cardiovascular Metabolism.
    Daniel Finke, Markus B Heckmann, Norbert Frey, Lorenz H Lehmann.
      Cardiovascular diseases have multifactorial causes. Classical cardiovascular risk factors, such as arterial hypertension, smoking, hyperlipidemia, and diabetes associate with the development of vascular stenoses and coronary heart disease. Further comorbidities and its impact on cardiovascular metabolism have gotten more attention recently. Thus, also cancer biology may affect the heart, apart from cardiotoxic side effects of chemotherapies. Cancer is a systemic disease which primarily leads to metabolic alterations within the tumor. An emerging number of preclinical and clinical studies focuses on the interaction between cancer and a maladaptive crosstalk to the heart. Cachexia and sarcopenia can have dramatic consequences for many organ functions, including cardiac wasting and heart failure. These complications significantly increase mortality and morbidity of heart failure and cancer patients. There are concurrent metabolic changes in fatty acid oxidation (FAO) and glucose utilization in heart failure as well as in cancer, involving central molecular regulators, such as PGC-1α. Further, specific inflammatory cytokines (IL-1β, IL-6, TNF-α, INF-β), non-inflammatory cytokines (myostatin, SerpinA3, Ataxin-10) and circulating metabolites (D2-HG) may mediate a direct and maladaptive crosstalk of both diseases. Additionally, cancer therapies, such as anthracyclines and angiogenesis inhibitors target common metabolic mechanisms in cardiomyocytes and malignant cells. This review focuses on cardiovascular, cancerous, and cancer therapy-associated alterations on the systemic and cardiac metabolic state.
    Keywords:  cancer metabolism; cardiac metabolism; cardio-oncology; cytokines; heart failure; inflammation; metabolic shift; second messenger
    DOI:  https://doi.org/10.3389/fphys.2021.729713
  3. World J Hepatol. 2021 Nov 27. 13(11): 1512-1533
    Fatty acid metabolism and acyl-CoA synthetases in the liver-gut axis.
    Yunxia Ma, Miljana Nenkov, Yuan Chen, Adrian T Press, Elke Kaemmerer, Nikolaus Gassler.
      Fatty acids are energy substrates and cell components which participate in regulating signal transduction, transcription factor activity and secretion of bioactive lipid mediators. The acyl-CoA synthetases (ACSs) family containing 26 family members exhibits tissue-specific distribution, distinct fatty acid substrate preferences and diverse biological functions. Increasing evidence indicates that dysregulation of fatty acid metabolism in the liver-gut axis, designated as the bidirectional relationship between the gut, microbiome and liver, is closely associated with a range of human diseases including metabolic disorders, inflammatory disease and carcinoma in the gastrointestinal tract and liver. In this review, we depict the role of ACSs in fatty acid metabolism, possible molecular mechanisms through which they exert functions, and their involvement in hepatocellular and colorectal carcinoma, with particular attention paid to long-chain fatty acids and small-chain fatty acids. Additionally, the liver-gut communication and the liver and gut intersection with the microbiome as well as diseases related to microbiota imbalance in the liver-gut axis are addressed. Moreover, the development of potentially therapeutic small molecules, proteins and compounds targeting ACSs in cancer treatment is summarized.
    Keywords:  Acyl-CoA synthetases; Liver-gut axis ; Long-chain fatty acids; Microbiota; Short-chain fatty acids
    DOI:  https://doi.org/10.4254/wjh.v13.i11.1512
  4. Front Cardiovasc Med. 2021 ;8 771298
    Mitochondrial Transfer in Cardiovascular Disease: From Mechanisms to Therapeutic Implications.
    Jun Chen, Jinjie Zhong, Lin-Lin Wang, Ying-Ying Chen.
      Mitochondrial dysfunction has been proven to play a critical role in the pathogenesis of cardiovascular diseases. The phenomenon of intercellular mitochondrial transfer has been discovered in the cardiovascular system. Studies have shown that cell-to-cell mitochondrial transfer plays an essential role in regulating cardiovascular system development and maintaining normal tissue homeostasis under physiological conditions. In pathological conditions, damaged cells transfer dysfunctional mitochondria toward recipient cells to ask for help and take up exogenous functional mitochondria to alleviate injury. In this review, we summarized the mechanism of mitochondrial transfer in the cardiovascular system and outlined the fate and functional role of donor mitochondria. We also discussed the advantage and challenges of mitochondrial transfer strategies, including cell-based mitochondrial transplantation, extracellular vesicle-based mitochondrial transplantation, and naked mitochondrial transplantation, for the treatment of cardiovascular disorders. We hope this review will provide perspectives on mitochondrial-targeted therapeutics in cardiovascular diseases.
    Keywords:  cardiovascular disease; extracellular vesicles; mitochondria; mitochondrial transfer; mitochondrial transplantation; tunneling nanotubes
    DOI:  https://doi.org/10.3389/fcvm.2021.771298
  5. PLoS One. 2021 ;16(12): e0261572
    In vivo identification and validation of novel potential predictors for human cardiovascular diseases.
    Omar T Hammouda, Meng Yue Wu, Verena Kaul, Jakob Gierten, Thomas Thumberger, Joachim Wittbrodt.
      Genetics crucially contributes to cardiovascular diseases (CVDs), the global leading cause of death. Since the majority of CVDs can be prevented by early intervention there is a high demand for the identification of predictive causative genes. While genome wide association studies (GWAS) correlate genes and CVDs after diagnosis and provide a valuable resource for such causative candidate genes, often preferentially those with previously known or suspected function are addressed further. To tackle the unaddressed blind spot of understudied genes, we particularly focused on the validation of human heart phenotype-associated GWAS candidates with little or no apparent connection to cardiac function. Building on the conservation of basic heart function and underlying genetics from fish to human we combined CRISPR/Cas9 genome editing of the orthologs of human GWAS candidates in isogenic medaka with automated high-throughput heart rate analysis. Our functional analyses of understudied human candidates uncovered a prominent fraction of heart rate associated genes from adult human patients impacting on the heart rate in embryonic medaka already in the injected generation. Following this pipeline, we identified 16 GWAS candidates with potential diagnostic and predictive power for human CVDs.
    DOI:  https://doi.org/10.1371/journal.pone.0261572
  6. Cell Signal. 2021 Dec 10. pii: S0898-6568(21)00302-8. [Epub ahead of print] 110213
    Protein phosphatase 2A in the healthy and failing heart: New insights and therapeutic opportunities.
    Nicola M Sergienko, Daniel G Donner, Lea M D Delbridge, Julie R McMullen, Kate L Weeks.
      Protein phosphatases have emerged as critical regulators of phosphoprotein homeostasis in settings of health and disease. Protein phosphatase 2A (PP2A) encompasses a large subfamily of enzymes that remove phosphate groups from serine/threonine residues within phosphoproteins. The heterogeneity in PP2A structure, which arises from the grouping of different catalytic, scaffolding and regulatory subunit isoforms, creates distinct populations of catalytically active enzymes (i.e. holoenzymes) that localise to different parts of the cell. This structural complexity, combined with other regulatory mechanisms, such as interaction of PP2A heterotrimers with accessory proteins and post-translational modification of the catalytic and/or regulatory subunits, enables PP2A holoenzymes to target phosphoprotein substrates in a highly specific manner. In this review, we summarise the roles of PP2A in cardiac physiology and disease. PP2A modulates numerous processes that are vital for heart function including calcium handling, contractility, β-adrenergic signalling, metabolism and transcription. Dysregulation of PP2A has been observed in human cardiac disease settings, including heart failure and atrial fibrillation. Efforts are underway, particularly in the cancer field, to develop therapeutics targeting PP2A activity. The development of small molecule activators of PP2A (SMAPs) and other compounds that selectively target specific PP2A holoenzymes (e.g. PP2A/B56α and PP2A/B56ε) will improve understanding of the function of different PP2A species in the heart, and may lead to the development of therapeutics for normalising aberrant protein phosphorylation in settings of cardiac remodelling and dysfunction.
    Keywords:  Heart failure; Kinases; PP2A; Protein phosphatase 2A; Therapies
    DOI:  https://doi.org/10.1016/j.cellsig.2021.110213
  7. Eur Heart J. 2021 12 14. 42(47): 4777-4780
    An update on triglyceride-rich lipoproteins and their remnants in atherosclerotic cardiovascular disease.
    Filippo Crea.
      
    DOI:  https://doi.org/10.1093/eurheartj/ehab844
  8. Front Cardiovasc Med. 2021 ;8 774619
    New Insights Into the Role of Mitochondria Quality Control in Ischemic Heart Disease.
    Yanguo Xin, Xiaodong Zhang, Jingye Li, Hui Gao, Jiayu Li, Junli Li, Wenyu Hu, Hongwei Li.
      IHD is a significant cause of mortality and morbidity worldwide. In the acute phase, it's demonstrated as myocardial infarction and ischemia-reperfusion injury, while in the chronic stage, the ischemic heart is mainly characterised by adverse myocardial remodelling. Although interventions such as thrombolysis and percutaneous coronary intervention could reduce the death risk of these patients, the underlying cellular and molecular mechanisms need more exploration. Mitochondria are crucial to maintain the physiological function of the heart. During IHD, mitochondrial dysfunction results in the pathogenesis of ischemic heart disease. Ischemia drives mitochondrial damage not only due to energy deprivation, but also to other aspects such as mitochondrial dynamics, mitochondria-related inflammation, etc. Given the critical roles of mitochondrial quality control in the pathological process of ischemic heart disease, in this review, we will summarise the efforts in targeting mitochondria (such as mitophagy, mtROS, and mitochondria-related inflammation) on IHD. In addition, we will briefly revisit the emerging therapeutic targets in this field.
    Keywords:  inflammation; metabolism; mitochondria; myocardial infarction; remodelling
    DOI:  https://doi.org/10.3389/fcvm.2021.774619
  9. Curr Opin Lipidol. 2021 Dec 13.
    Very long-chain saturated fatty acids and diabetes and cardiovascular disease.
    Rozenn N Lemaitre, Irena B King.
       PURPOSE OF REVIEW: In contrast to other saturated fatty acids, very long-chain saturated fatty acids (VLSFAs) have received limited attention The purpose of this review is to summarize the associations of VLSFAs, including arachidic acid, behenic acid, and lignoceric acid, with cardiovascular disease outcomes and type 2 diabetes; to discuss the findings implications; and to call for future studies of the VLSFAs.
    RECENT FINDINGS: Increased levels of circulating VLSFAs have been found associated with lower risks of incident heart failure, atrial fibrillation, coronary heart disease, mortality, sudden cardiac arrest, type 2 diabetes, and with better aging. The VLSFA associations are paralleled by associations of plasma ceramide and sphingomyelin species carrying a VLSFA with lower risks of heart failure, atrial fibrillation, and mortality, suggesting VLSFAs affect the biological activity of ceramides and sphingomyelins thereby impacting health. For diabetes, there is no such parallel and the associations of VLSFAs with diabetes may be confounded or mediated by triglyceride and circulating palmitic acid, possible biomarkers of de novo lipogenesis.
    SUMMARY: In many ways, the epidemiology has preceded our knowledge of VLSFAs biology. We hope this review will spur interest from the research community in further studying these potentially beneficial fatty acids.
    DOI:  https://doi.org/10.1097/MOL.0000000000000806
  10. J Mol Cell Cardiol. 2021 Dec 13. pii: S0022-2828(21)00231-5. [Epub ahead of print]
    Hallmarks of exercised heart.
    Yan Qiu, Xue Pan, Yiwen Chen, Junjie Xiao.
      The benefits of exercise in humans on the heart have been well recognized for many years. Long-term endurance exercise training can induce physiologic cardiac hypertrophy with normal or enhanced heart function, and provide protective benefits in preventing heart failure. The heart-specific responses that occur during exercise are complex and highly variable. This review mainly focuses on the current understanding of the structural and functional cardiac adaptations to exercise as well as molecular pathways and signaling proteins responsible for these changes. Here, we summarize eight tentative hallmarks that represent common denominators of the exercised heart. These hallmarks are: cardiomyocyte growth, cardiomyocyte fate reprogramming, angiogenesis and lymphangiogenesis, mitochondrial remodeling, epigenetic alteration, enhanced endothelial function, quiescent cardiac fibroblast, and improved cardiac metabolism. A major challenge is to explore the underlying molecular mechanisms for cardio-protective effects of exercise, and to identify therapeutic targets for heart diseases.
    Keywords:  Cardiac adaptation; Exercise; Hallmarks; Physiologic cardiac hypertrophy
    DOI:  https://doi.org/10.1016/j.yjmcc.2021.12.004
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