bims-hafaim 2023-01-22 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2023‒01‒22
ten papers selected by
Kyle McCommis
Saint Louis University

Hypertrophic preconditioning attenuates myocardial ischemia/reperfusion injury through the deacetylation of isocitrate dehydrogenase 2.
Inhibiting O-GlcNAcylation impacts p38 and Erk1/2 signaling and perturbs cardiomyocyte hypertrophy.
Evaluation of coenzyme Q10 (CoQ10) deficiency and therapy in mouse models of cardiomyopathy.
Emerging role of mitophagy in heart failure: from molecular mechanism to targeted therapy.
S100a8/a9 contributes to sepsis-induced cardiomyopathy by activating ERK1/2-Drp1-mediated mitochondrial fission and respiratory dysfunction.
Safety and Tolerability of Nicotinamide Riboside in Heart Failure With Reduced Ejection Fraction.
Metabolomics and a Breath Sensor Identify Acetone as a Biomarker for Heart Failure.
Emerging concepts in heart failure management and treatment: focus on SGLT2 inhibitors in heart failure with preserved ejection fraction.
Targeting the Autophagy-Lysosome Pathway in a Pathophysiologically Relevant Murine Model of Reversible Heart Failure.
Novel insights into the involvement of mitochondrial fission/fusion in heart failure: From molecular mechanisms to targeted therapies.

Sci Bull (Beijing). 2021 Oct 30. pii: S2095-9273(21)00264-4. [Epub ahead of print]66(20): 2099-2114

Hypertrophic preconditioning attenuates myocardial ischemia/reperfusion injury through the deacetylation of isocitrate dehydrogenase 2.

Leilei Ma, Hongtao Shi, Yang Li, Wei Gao, Junjie Guo, Jianbing Zhu, Zheng Dong, Aijun Sun, Yunzeng Zou, Junbo Ge.

  To test the hypothesis that transient nonischemic stimulation of hypertrophy would render the heart resistant to subsequent ischemic stress, short-term transverse aortic constriction (TAC) was performed in mice and then withdrawn for several days by aortic debanding, followed by subsequent myocardial exposure to ischemia/reperfusion (I/R). Following I/R injury, the myocardial infarct size and apoptosis were markedly reduced, and contractile function was significantly improved in the TAC preconditioning group compared with the control group. Mechanistically, hypertrophic preconditioning remarkably alleviated I/R-induced oxidative stress, as evidenced by the increased reduced nicotinamide adenine dinucleotide phosphate (NADPH)/nicotinamide adenine dinucleotide phosphate (NADP) ratio, increase in the reduced glutathione (GSH)/oxidized glutathione (GSSH) ratio, and reduced mitochondrial reactive oxygen species (ROS) production. Moreover, TAC preconditioning inhibited caspase-3 activation and mitigated the mitochondrial impairment by deacetylating isocitrate dehydrogenase 2 (IDH2) via a sirtuin 3 (SIRT3)-dependent mechanism. In addition, the expression of a genetic deacetylation mimetic IDH2 mutant (IDH2 K413R) in cardiomyocytes, which increased IDH2 enzymatic activity and decreased mitochondrial ROS production, and ameliorated I/R injury, whereas the expression of a genetic acetylation mimetic (IDH2 K413Q) in cardiomyocytes abolished these protective effects of hypertrophic preconditioning. Furthermore, both the activity and expression of the SIRT3 protein were markedly increased in preconditioned mice exposed to I/R. Treatment with an adenovirus encoding SIRT3 partially emulated the actions of hypertrophic preconditioning, whereas genetic ablation of SIRT3 in mice blocked the cardioprotective effects of hypertrophic preconditioning. The present study identifies hypertrophic preconditioning as a novel endogenous self-defensive and cardioprotective strategy for cardiac I/R injury that induces IDH2 deacetylation through a SIRT3-dependent mechanism. A therapeutic strategy targeting IDH2 may be a promising treatment for cardiac ischemic injury.

Keywords:  Acetylation; Hypertrophic preconditioning; IDH2; Ischemia/reperfusion injury; SIRT3

DOI:  https://doi.org/10.1016/j.scib.2021.04.008
J Biol Chem. 2023 Jan 12. pii: S0021-9258(23)00039-X. [Epub ahead of print] 102907

Inhibiting O-GlcNAcylation impacts p38 and Erk1/2 signaling and perturbs cardiomyocyte hypertrophy.

Kyriakos N Papanicolaou, Jessica Jung, Deepthi Ashok, Wenxi Zhang, Amir Modaressanavi, Eddie Avila, D Brian Foster, Natasha E Zachara, Brian O'Rourke.

  The dynamic cycling of O-linked N-Acetylglucosamine (O-GlcNAc) on and off Ser/Thr residues of intracellular proteins, termed O-GlcNAcylation, is mediated by the conserved enzymes O-GlcNAc Transferase (OGT) and O-GlcNAcase (OGA). O-GlcNAc cycling is important in homeostatic and stress responses and its perturbation sensitizes the heart to ischemic and other injuries. Despite considerable progress, many molecular pathways impacted by O-GlcNAcylation in the heart remain unclear. The mitogen-activated protein kinase (MAPK) pathway is a central signaling cascade that coordinates developmental, physiological, and pathological responses in the heart. The developmental or adaptive arm of MAPK signaling is primarily mediated by Erk kinases while the pathophysiologic arm is mediated by p38 and Jnk kinases. Here, we examine whether O-GlcNAcylation affects MAPK signaling in cardiac myocytes, focusing on Erk1/2 and p38 in basal and hypertrophic conditions induced by phenylephrine. Using metabolic labeling of glycans coupled with alkyne-azide 'click' chemistry we found that Erk1/2 and p38 are O-GlcNAcylated. Supporting the regulation of p38 by O-GlcNAcylation, the OGT inhibitor, OSMI-1, triggers the phosphorylation of p38, an event that involves the NOX2-Ask1-MKK3/6 signaling axis but also the non-canonical activator Tab1. Additionally, OGT inhibition blocks the phenylephrine-induced phosphorylation of Erk1/2. Consistent with perturbed MAPK signaling, OSMI-1-treated cardiomyocytes have a blunted hypertrophic response to phenylephrine, downregulation of cTnT expression (encoding a key component of the contractile apparatus), and increased expression of maladaptive natriuretic factors Anp and Bnp. Collectively, these studies highlight new roles for O-GlcNAcylation in maintaining a balanced activity of Erk1/2 and p38 MAPKs during hypertrophic growth responses in cardiomyocytes.

Keywords:  Creb; Gata4; Hsp27; Hsp90; Keywords: OGT; MKK3/6; OGA; OSMI; TMG; Tab1

DOI:  https://doi.org/10.1016/j.jbc.2023.102907
J Cardiovasc Pharmacol. 2023 Jan 20.

Evaluation of coenzyme Q10 (CoQ10) deficiency and therapy in mouse models of cardiomyopathy.

Tian-Tian Pu, Wei Wu, Pei-Da Liang, Jin-Chan Du, Sheng-Li Han, Xiu-Ling Deng, Xiao-Jun Du.

ABSTRACT: Mitochondrial dysfunction plays a key role in the development of heart failure, but targeted therapeutic interventions remain elusive. Previous studies have shown coenzyme Q10 (CoQ10) insufficiency in patients with heart disease with undefined mechanism, and modest effectiveness of CoQ10 supplement therapy. Using two transgenic mouse models of cardiomyopathy owing to cardiac overexpression of Mst1 (Mst1-TG) or β2-adrenoceptor (β2AR-TG), we studied changes in cardiac CoQ10 content and alterations in CoQ10 biosynthesis genes. We also studied in Mst1-TG mice effects of CoQ10, delivered by oral or injection regimens, on both cardiac CoQ10 content and cardiomyopathy phenotypes. HPLC and RNA-sequencing revealed in both models significant reduction in cardiac content of CoQ10 and downregulation of majority of genes encoding CoQ10 biosynthesis enzymes. Mst1-TG mice with 70% reduction in cardiac CoQ10 were treated with CoQ10 either by oral gavage or i.p. injection for 4-8 weeks. Oral regimens failed in increasing cardiac CoQ10 content, whereas injection regimen effectively restored cardiac CoQ10 level in a time-dependent manner. However, CoQ10 restoration in Mst1-TG mice did not correct mitochondrial dysfunction measured by energy metabolism, downregulated expression of marker proteins and oxidative stress, nor to preserve cardiac contractile function. In conclusion, mouse models of cardiomyopathy exhibited myocardial CoQ10 deficiency likely due to suppressed endogenous synthesis of CoQ10. In contrast to ineffectiveness of oral administration, CoQ10 administration by injection regimen in cardiomyopathy mice restored cardiac CoQ10 content, which, however, failed in achieving detectable efficacy at molecular and global functional levels.

DOI: https://doi.org/10.1097/FJC.0000000000001401
Cell Cycle. 2023 Jan 19. 1-13

Emerging role of mitophagy in heart failure: from molecular mechanism to targeted therapy.

Yu Liu, Yizhou Wang, Yingfei Bi, Zhiqiang Zhao, Shuai Wang, Shanshan Lin, Zhihua Yang, Xianliang Wang, Jingyuan Mao.

  Heart failure is defined as a drop in heart's pump function, accounting for reduced blood output and venous stasis, and constitutes the end stage of various cardiovascular diseases. Although mild mitochondrial dysfunction may hinder cardiomyocyte metabolism and impair myocardial function, severe mitochondrial injury is accompanied by cardiomyocyte apoptosis, leading to irreversible damage of the heart. Selective autophagy of mitochondria, or mitophagy, serves to rapidly remove dysfunctional mitochondria and restore the health of the mitochondrial population within cells by allowing reutilization of degradative substrates such as amino acids, fatty acids, and nucleotides. Although mitophagy represents a protective program that prevents the accumulation of poorly structured or damaged mitochondria, excessive mitophagy leads to mitochondrial population decline, impaired oxidative phosphorylation, and decreased ATP production. In this review, we first discuss the molecular underpinnings of mitophagy and the roles of different mitophagy adaptors. Then, the multiple and complex influence of mitophagy on heart failure is summarized. Finally, novel pharmacological strategies targeting mitophagy to relieve heart failure are briefly summarized.

Keywords:  Bnip3; FUNDC1; Heart failure; Parkin; mitophagy

DOI:  https://doi.org/10.1080/15384101.2023.2167949
Int Immunopharmacol. 2023 Jan 16. pii: S1567-5769(23)00039-5. [Epub ahead of print]115 109716

S100a8/a9 contributes to sepsis-induced cardiomyopathy by activating ERK1/2-Drp1-mediated mitochondrial fission and respiratory dysfunction.

Feng Wu, Yan-Ting Zhang, Fei Teng, Hui-Hua Li, Shu-Bin Guo.

  Sepsis-induced cardiomyopathy (SIC) is the main complication and a leading cause of death in intensive care units. S100a8/a9 is a calcium-binding protein that participates in various inflammatory diseases; however, its role in sepsis-induced cardiomyopathy and the underlying mechanism remains to be explored. Here, septic cardiomyopathy was induced with cecal ligation and puncture (CLP) in S100a9-knockout (KO) mice lacking the heterodimer S100a8/a9 or wild-type (WT) mice administered with an S100a9-specific inhibitor Paquinimod (Paq), which prevents the binding of S100a9 toTLR4. Our results showed that S100a8/a9 expression in the heart peaked 24 h following the CLP operation, declined at 48 h and returned to baseline at 72 h. Loss of S100a9 by knockout in mice protected against CLP-induced mortality, cardiac dysfunction, myocyte apoptosis, recruitment of Mac-2+ macrophages, superoxide production, and the expression of pro-inflammatory cytokines genes compared with WT mice. Moreover, S100a9-KO significantly attenuated CLP-induced activation of the ERK1/2-Drp1 (S616) pathway, excessive mitochondrial fission, and mitochondrial respiration dysfunction. In contrast, activation of ERK1/2 with its agonist tBHQ reversed the inhibitory effects of S100a9-knockout on CLP-induced cardiomyopathy and mitochondrial dysfunction. Finally, administration of Paq to WT mice markedly prevented the CLP-induced cardiomyopathy mitochondrial fission and dysfunction compared with vehicle control. In summary, our data reveal, for the first time, that S100a8/a9 plays a critical role in mediating SIC, presumably by activating TLR4-ERK1/2-Drp1-dependent mitochondrial fission and dysfunction and highlight that blockage of S100a8/a9 may be a promising therapeutic strategy to prevent SIC in patients with sepsis.

Keywords:  Cardiomyopathy; ERK-Drp1; Mitochondrial fission; Mitochondrial respiratory dysfunction; S100a8/a9; Sepsis

DOI:  https://doi.org/10.1016/j.intimp.2023.109716
JACC Basic Transl Sci. 2022 Dec;7(12): 1183-1196

Safety and Tolerability of Nicotinamide Riboside in Heart Failure With Reduced Ejection Fraction.

Dennis D Wang, Sophia E Airhart, Bo Zhou, Laura M Shireman, Siyi Jiang, Carolina Melendez Rodriguez, James N Kirkpatrick, Danny D Shen, Rong Tian, Kevin D O'Brien.

  The mitochondrial dysfunction characteristic of heart failure (HF) is associated with changes in intracellular nicotinamide adenine dinucleotide (NAD+) and NADH levels. Raising NAD+ levels with the NAD+ precursor, nicotinamide riboside (NR), may represent a novel HF treatment. In this 30-participant trial of patients with clinically stable HF with reduced ejection fraction, NR, at a dose of 1,000 mg twice daily, appeared to be safe and well tolerated, and approximately doubled whole blood NAD+ levels. Intraindividual NAD+ increases in response to NR correlated with increases in peripheral blood mononuclear cell basal (R 2 = 0.413, P = 0.003) and maximal (R 2 = 0.434, P = 0.002) respiration, and with decreased NLRP3 expression (R 2 = 0.330, P = 0.020). (Nicotinamide Riboside in Systolic Heart Failure; NCT03423342).

Keywords:  AE, adverse event; E/e′, ratio of the early transmitral flow velocity to the early diastolic tissue velocity; GLS, global longitudinal strain; HF, heart failure; HFrEF; HFrEF, heart failure with reduced rejection fraction; IL, interleukin; LV, left ventricular; NAD+; NAD+, nicotinamide adenine dinucleotide; NLRP3, NOD-like receptor family pyrin domain containing 3; NR; NR, nicotinamide riboside; PBMC, peripheral blood mononuclear cell; TNF, tumor necrosis factor; heart failure with reduced ejection fraction; mitochondrial dysfunction; nicotinamide adenine dinucleotide; nicotinamide riboside; sterile inflammation

DOI:  https://doi.org/10.1016/j.jacbts.2022.06.012
Biomolecules. 2022 Dec 21. pii: 13. [Epub ahead of print]13(1):

Metabolomics and a Breath Sensor Identify Acetone as a Biomarker for Heart Failure.

Patrick A Gladding, Maxine Cooper, Renee Young, Suzanne Loader, Kevin Smith, Erica Zarate, Saras Green, Silas G Villas Boas, Phillip Shepherd, Purvi Kakadiya, Eric Thorstensen, Christine Keven, Margaret Coe, Mia Jüllig, Edmond Zhang, Todd T Schelegel.

  BACKGROUND: Multi-omics delivers more biological insight than targeted investigations. We applied multi-omics to patients with heart failure with reduced ejection fraction (HFrEF).METHODS: 46 patients with HFrEF and 20 controls underwent metabolomic profiling, including liquid/gas chromatography mass spectrometry (LC-MS/GC-MS) and solid-phase microextraction (SPME) volatilomics in plasma and urine. HFrEF was defined using left ventricular global longitudinal strain, ejection fraction and NTproBNP. A consumer breath acetone (BrACE) sensor validated results in n = 73.
RESULTS: 28 metabolites were identified by GCMS, 35 by LCMS and 4 volatiles by SPME in plasma and urine. Alanine, aspartate and glutamate, citric acid cycle, arginine biosynthesis, glyoxylate and dicarboxylate metabolism were altered in HFrEF. Plasma acetone correlated with NT-proBNP (r = 0.59, 95% CI 0.4 to 0.7), 2-oxovaleric and cis-aconitic acid, involved with ketone metabolism and mitochondrial energetics. BrACE > 1.5 ppm discriminated HF from other cardiac pathology (AUC 0.8, 95% CI 0.61 to 0.92, p < 0.0001).
CONCLUSION: Breath acetone discriminated HFrEF from other cardiac pathology using a consumer sensor, but was not cardiac specific.

Keywords:  heart failure with reduced ejection fraction

DOI:  https://doi.org/10.3390/biom13010013
Drugs Context. 2023 ;pii: 2022-7-1. [Epub ahead of print]12

Emerging concepts in heart failure management and treatment: focus on SGLT2 inhibitors in heart failure with preserved ejection fraction.

Andrea Beatriz De Lorenzi, Edgardo Kaplinsky, Marx Rivera Zambrano, Laia Tomás Chaume, Joan Monell Rosas.

  The role of sodium-glucose cotransporter 2 inhibitors (SLTG2i), developed initially as glucose-lowering agents, has represented a novelty in patients with heart failure (HF) and reduced ejection fraction (HFrEF) since dapagliflozin (DAPA-HF study) and empagliflozin (EMPEROR-Reduced study) were able to reduce morbidity and mortality in this setting regardless of the presence or absence of diabetes. In previous large clinical trials (EMPA-REG OUTCOME study, CANVAS, DECLARE-TIMI 58), SGLT2i have been shown to attenuate HF progression expressed by reducing the risk of HF hospitalizations in patients with type 2 diabetes mellitus mostly without HF at baseline. This benefit was then corroborated with positive results in HF outcomes (cardiovascular mortality and HF hospitalizations) in patients with HF with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved (empagliflozin) and DELIVER (dapagliflozin) trials. Several biological mechanisms apart from the glycosuria are attributed to these agents in this last context, including anti-inflammatory effects, reduction of fibrosis and apoptosis, improvement of myocardial metabolism, mitochondrial function optimization, and oxidative stress protection. Moreover, SGLT2i can also improve ventricular loading conditions by forcing diuresis and natriuresis, and by enhancing vascular and renal function. In addition, SGLT2i can reduce myocardial passive stiffness (diastolic function) by enforcing the phosphorylation of myofilament modulatory proteins. This article provided an overview of the main pathophysiological characteristics of HFpEF and of the diverse mechanisms of action of SGLT2i in this setting. The supporting clinical evidence of SGLT2i in HFpEF (EMPEROR-Preserved and DELIVER trials) is also reviewed. This article is part of the Emerging concepts in heart failure management and treatment Special Issue: https://www.drugsincontext.com/special_issues/emerging-concepts-in-heart-failure-management-and-treatment.

Keywords:  DELIVER; EMPEROR-Preserved; SGLT2 inhibitors; dapagliflozin; empagliflozin; heart failure with preserved ejection fraction

DOI:  https://doi.org/10.7573/dic.2022-7-1
JACC Basic Transl Sci. 2022 Dec;7(12): 1214-1228

Targeting the Autophagy-Lysosome Pathway in a Pathophysiologically Relevant Murine Model of Reversible Heart Failure.

Sarah Evans, Xiucui Ma, Xiqiang Wang, Yana Chen, Chen Zhao, Carla J Weinheimer, Attila Kovacs, Brian Finck, Abhinav Diwan, Douglas L Mann.

  The key biological "drivers" that are responsible for reverse left ventricle (LV) remodeling are not well understood. To gain an understanding of the role of the autophagy-lysosome pathway in reverse LV remodeling, we used a pathophysiologically relevant murine model of reversible heart failure, wherein pressure overload by transaortic constriction superimposed on acute coronary artery (myocardial infarction) ligation leads to a heart failure phenotype that is reversible by hemodynamic unloading. Here we show transaortic constriction + myocardial infarction leads to decreased flux through the autophagy-lysosome pathway with the accumulation of damaged proteins and organelles in cardiac myocytes, whereas hemodynamic unloading is associated with restoration of autophagic flux to normal levels with incomplete removal of damaged proteins and organelles in myocytes and reverse LV remodeling, suggesting that restoration of flux is insufficient to completely restore myocardial proteostasis. Enhancing autophagic flux with adeno-associated virus 9-transcription factor EB resulted in more favorable reverse LV remodeling in mice that had undergone hemodynamic unloading, whereas overexpressing transcription factor EB in mice that have not undergone hemodynamic unloading leads to increased mortality, suggesting that the therapeutic outcomes of enhancing autophagic flux will depend on the conditions in which flux is being studied.

Keywords:  AAV9, adeno-associated virus 9; CMV, cytomegalovirus; CQ, chloroquine; GFP, green red fluorescent protein; HF, heart failure; HF-DB, TAC + MI mice that have undergone debanding; LFEF, left ventricular ejection fraction; LV, left ventricle; MI, myocardial infarction; RFP, red fluorescent protein; TAC, transaortic constriction; TEM, transmission electron microscopic; TFEB, transcription factor EB; autophagy; dsDNA, double stranded DNA; eGFP, enhanced green fluorescent protein; mTOR, mammalian target of rapamycin; reverse left ventricle remodeling

DOI:  https://doi.org/10.1016/j.jacbts.2022.06.003
Cell Stress Chaperones. 2023 Jan 18.

Novel insights into the involvement of mitochondrial fission/fusion in heart failure: From molecular mechanisms to targeted therapies.

Xinxin Liu, Chenchen Guo, Qiming Zhang.

  Mitochondria are dynamic organelles that alter their morphology through fission (fragmentation) and fusion (elongation). These morphological changes correlate highly with mitochondrial functional adaptations to stressors, such as hypoxia, pressure overload, and inflammation, and are important in the setting of heart failure. Pathological mitochondrial remodeling, characterized by increased fission and reduced fusion, is associated with impaired mitochondrial respiration, increased mitochondrial oxidative stress, abnormal cytoplasmic calcium handling, and increased cardiomyocyte apoptosis. Considering the impact of the mitochondrial morphology on mitochondrial behavior and cardiomyocyte performance, altered mitochondrial dynamics could be expected to induce or exacerbate the pathogenesis and progression of heart failure. However, whether alterations in mitochondrial fission and fusion accelerate or retard the progression of heart failure has been the subject of intense debate. In this review, we first describe the physiological processes and regulatory mechanisms of mitochondrial fission and fusion. Then, we extensively discuss the pathological contributions of mitochondrial fission and fusion to heart failure. Lastly, we examine potential therapeutic approaches targeting mitochondrial fission/fusion to treat patients with heart failure.

Keywords:  DRP1; Heart failure; MFN1/2; Mitochondrial fission; Mitochondrial fusion; OPA1

DOI:  https://doi.org/10.1007/s12192-023-01321-4