bims-hafaim 2023-11-19 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2023‒11‒19
ten papers selected by
Kyle McCommis, Saint Louis University

Stimulates Short-Chain Dehydrogenase/Reductase Proteins to Alleviate Heart Failure Independent of Mitochondrial Protein Deacetylation.
Obesity is a Major Determinant of Impaired Cardiac Energy Metabolism in Heart Failure with Preserved Ejection Fraction.
FOXO1 reduces STAT3 activation and causes impaired mitochondrial quality control in diabetic cardiomyopathy.
Exogenous NADPH exerts a positive inotropic effect and enhances energy metabolism via SIRT3 in pathological cardiac hypertrophy and heart failure.
Dietary branched-chain amino acids get to the heart of H3K23Pr.
Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function.
Effect of empagliflozin on cardiac remodelling in South Asian and non-South Asian individuals: insights from the EMPA-HEART CardioLink-6 randomised clinical trial.
Nicotinamide Riboside, an NAD + Precursor, Protects Against Cardiac Mitochondrial Dysfunction in Fetal Guinea Pigs Exposed to Gestational Hypoxia.
Targeting mitochondrial shape: at the heart of cardioprotection.
Combined fructose and sucrose consumption from an early age aggravates cardiac oxidative damage and causes a dilated cardiomyopathy in SHR rats.

Circulation. 2023 Nov 15.

Stimulates Short-Chain Dehydrogenase/Reductase Proteins to Alleviate Heart Failure Independent of Mitochondrial Protein Deacetylation.

Matthew A Walker, Hongye Chen, Aprajita Yadav, Julia Ritterhoff, Outi Villet, Tim McMillen, Yuliang Wang, Hayley Purcell, Danijel Djukovic, Daniel Raftery, Nina Isoherranen, Rong Tian.

  BACKGROUND: Strategies to increase cellular NAD+ (oxidized nicotinamide adenine dinucleotide) level have prevented cardiac dysfunction in multiple models of heart failure, but molecular mechanisms remain unclear. Little is known about the benefits of NAD+-based therapies in failing hearts after the symptoms of heart failure have appeared. Most pretreatment regimens suggested mechanisms involving activation of sirtuin, especially Sirt3 (sirtuin 3), and mitochondrial protein acetylation.METHODS: We induced cardiac dysfunction by pressure overload in SIRT3-deficient (knockout) mice and compared their response with nicotinamide riboside chloride treatment with wild-type mice. To model a therapeutic approach, we initiated the treatment in mice with established cardiac dysfunction and found nicotinamide riboside chloride improved mitochondrial function and blunted heart failure progression. Similar benefits were observed in wild-type and knockout mice. Boosting NAD+ level improved the function of NAD(H) redox-sensitive SDR (short-chain dehydrogenase/reductase) family proteins. Upregulation of Mrpp2 (mitochondrial ribonuclease P protein 2), a multifunctional SDR protein and a subunit of mitochondrial ribonuclease P, improves mitochondrial DNA transcripts processing and electron transport chain function. Activation of SDRs in the retinol metabolism pathway stimulates RXRα (retinoid X receptor α)/PPARα (proliferator-activated receptor α) signaling and restores mitochondrial oxidative metabolism. Downregulation of Mrpp2 and impaired mitochondrial ribonuclease P were found in human failing hearts, suggesting a shared mechanism of defective mitochondrial biogenesis in mouse and human heart failure.
CONCLUSIONS: These findings identify SDR proteins as important regulators of mitochondrial function and molecular targets of NAD+-based therapy. Furthermore, the benefit is observed regardless of Sirt3-mediated mitochondrial protein deacetylation, a widely held mechanism for NAD+-based therapy for heart failure. The data also show that NAD+-based therapy can be useful in pre-existing heart failure.

Keywords:  NAD+; heart failure; mitochondria; nicotinamide riboside; short-chain dehydrogenase; sirtuin

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.066039
J Pharmacol Exp Ther. 2023 Nov 17. pii: JPET-AR-2023-001791. [Epub ahead of print]

Obesity is a Major Determinant of Impaired Cardiac Energy Metabolism in Heart Failure with Preserved Ejection Fraction.

Berna Güven, Qiuyu Sun, Cory S Wagg, Amanda Almeida de Oliveira, Heidi Silver, Kaya L Persad, Arzu Onay-Besikci, Jennie Vu, Gavin Y Oudit, Gary D Lopaschuk.

  Heart failure with preserved ejection fraction (HFpEF) is a major health problem with limited treatment options. Although optimizing cardiac energy metabolism is a potential approach to treating heart failure, it is poorly understood what alterations in cardiac energy metabolism actually occur in HFpEF. To determine this, we used mice in which HFpEF was induced using an obesity and hypertension HFpEF protocol for 10 weeks. Next, carvedilol, a third-generation β-blocker and a biased agonist that exhibits agonist-like effects through β arrestins by activating extracellular signal-regulated kinase (ERK), was used to decrease one of these parameters, namely hypertension. Heart function was evaluated by invasive pressure-volume loops and echocardiography, as well as by ex vivo working heart perfusions. Glycolysis and oxidation rates of glucose, fatty acids, and ketones were measured in the isolated working hearts. The development of HFpEF was associated with a dramatic decrease in cardiac glucose oxidation rates, with a parallel increase in palmitate oxidation rates. Carvedilol treatment decreased the development of HFpEF, but had no major effect on cardiac energy substrate metabolism. Carvedilol treatment did increase the expression of cardiac β arrestin 2 and proteins involved in mitochondrial biogenesis. Decreasing body weight in obese HFpEF mice increased glucose oxidation and improved heart function. This suggests that the dramatic energy metabolic changes in HFpEF mice hearts are primarily due to the obesity component of the HFpEF model. Significance Statement Metabolic inflexibility occurs in HFpEF mice hearts. Lowering blood pressure improves heart function in HFpEF mice with no major effect on energy metabolism. Between hypertension and obesity, the latter appears to have the major role in HFpEF cardiac energetic changes. Carvedilol increases mitochondrial biogenesis and overall energy expenditure in HFpEF hearts.

Keywords:  Arrestins; Biased agonism; Carbohydrate metabolism; fatty acid metabolism; heart/cardiac

DOI:  https://doi.org/10.1124/jpet.123.001791
Diabetes Obes Metab. 2023 Nov 14.

FOXO1 reduces STAT3 activation and causes impaired mitochondrial quality control in diabetic cardiomyopathy.

Lu Zhou, Wating Su, Yafeng Wang, Yuefu Zhang, Zhongyuan Xia, Shaoqing Lei.

  AIMS: To investigate the role of FOXO1 in STAT3 activation and mitochondrial quality control in the diabetic heart.METHODS: Type 1 diabetes mellitus (T1DM) was induced in rats by a single intraperitoneal injection of 60 mg · kg-1 streptozotocin (STZ), while type 2 diabetes mellitus (T2DM) was induced in rats with a high-fat diet through intraperitoneal injection of 35 mg · kg-1 STZ. Primary neonatal mouse cardiomyocytes and H9c2 cells were exposed to low glucose (5.5 mM) or high glucose (HG; 30 mM) with or without treatment with the FOXO1 inhibitor AS1842856 (1 μM) for 24 hours. In addition, the diabetic db/db mice (aged 8 weeks) and sex- and age-matched non-diabetic db/+ mice were treated with vehicle or AS1842856 by oral gavage for 15 days at a dose of 5 mg · kg-1 · d-1 .
RESULTS: Rats with T1DM or T2DM had excessive cardiac FOXO1 activation, accompanied by decreased STAT3 activation. Immunofluorescence and immunoprecipitation analysis showed colocalization and association of FOXO1 and STAT3 under basal conditions in isolated cardiomyocytes. Selective inhibition of FOXO1 activation by AS1842856 or FOXO1 siRNA transfection improved STAT3 activation, mitophagy and mitochondrial fusion, and decreased mitochondrial fission in isolated cardiomyocytes exposed to HG. Transfection with STAT3 siRNA further reduced mitophagy, mitochondrial fusion and increased mitochondrial fission in HG-treated cardiomyocytes. AS1842856 alleviated cardiac dysfunction, pathological damage and improved STAT3 activation, mitophagy and mitochondrial dynamics in diabetic db/db mice. Additionally, AS1842856 improved mitochondrial function indicated by increased mitochondrial membrane potential and adenosine triphosphate production and decreased mitochondrial reactive oxygen species production in isolated cardiomyocytes exposed to HG.
CONCLUSIONS: Excessive FOXO1 activation during diabetes reduces STAT3 activation, with subsequent impairment of mitochondrial quality, ultimately promoting the development of diabetic cardiomyopathy.

Keywords:  FOXO1; STAT3; diabetic cardiomyopathy; mitochondrial fission; mitochondrial fusion; mitophagy

DOI:  https://doi.org/10.1111/dom.15369
EBioMedicine. 2023 Nov 09. pii: S2352-3964(23)00429-2. [Epub ahead of print]98 104863

Exogenous NADPH exerts a positive inotropic effect and enhances energy metabolism via SIRT3 in pathological cardiac hypertrophy and heart failure.

Ke Qian, Jie Tang, Yue-Juan Ling, Ming Zhou, Xin-Xin Yan, Yu Xie, Lu-Jia Zhu, Koju Nirmala, Kang-Yun Sun, Zheng-Hong Qin, Rui Sheng.

  BACKGROUND: Therapies are urgently required to ameliorate pathological cardiac hypertrophy and enhance cardiac function in heart failure. Our preliminary experiments have demonstrated that exogenous NADPH exhibits a positive inotropic effect on isolated heart. This study aims to investigate the positive inotropic effects of NADPH in pathological cardiac hypertrophy and heart failure, as well as the underlying mechanisms involved.METHODS: Endogenous plasma NADPH contents were determined in patients with chronic heart failure and control adults. The positive inotropic effects of NADPH were investigated in isolated toad heart or rat heart. The effects of NADPH were investigated in isoproterenol (ISO)-induced cardiac hypertrophy or transverse aortic constriction (TAC)-induced heart failure. The underlying mechanisms of NADPH were studied using SIRT3 knockout mice, echocardiography, Western blotting, transmission electron microscopy, and immunoprecipitation.
FINDINGS: The endogenous NADPH content in the blood of patients and animals with pathological cardiac hypertrophy or heart failure was significantly reduced compared with age-sex matched control subjects. Exogenous NADPH showed positive inotropic effects on the isolated normal and failing hearts, while antagonism of ATP receptor partially abolished the positive inotropic effect of NADPH. Exogenous NADPH administration significantly reduced heart weight indices, and improved cardiac function in the mice with pathological cardiac hypertrophy or heart failure. NADPH increased SIRT3 expression and activity, deacetylated target proteins, improved mitochondrial function and facilitated ATP production in the hypertrophic myocardium. Importantly, inhibition of SIRT3 abolished the positive inotropic effect of NADPH, and the anti-heart failure effect of NADPH was significantly reduced in the SIRT3 Knockout mice.
INTERPRETATION: Exogenous NADPH shows positive inotropic effect and improves energy metabolism via SIRT3 in pathological cardiac hypertrophy and heart failure. NADPH thus may be one of the potential candidates for the treatment of pathological cardiac hypertrophy or heart failure.
FUNDING: This work was supported by grants from the National Natural Science Foundation of China (No. 81973315, 82173811, 81730092), Natural Science Foundation of Jiangsu Higher Education (20KJA310008), Jiangsu Key Laboratory of Neuropsychiatric Diseases (BM2013003) and the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD).

Keywords:  Acetylation; Cardiac hypertrophy; Heart failure; NADPH; Positive inotropic effect; SIRT3

DOI:  https://doi.org/10.1016/j.ebiom.2023.104863
J Clin Invest. 2023 Nov 15. pii: e174953. [Epub ahead of print]133(22):

Dietary branched-chain amino acids get to the heart of H3K23Pr.

Christina Demetriadou, Daniel S Kantner, Nathaniel W Snyder.

Cardiac metabolism provides effects that extend beyond the transformation of energy for the heart to operate effectively. Some metabolites also function as signaling molecules and exert transcriptional changes. Heart failure is a progressive pathology in which these metabolite functions falter. In this issue of the JCI, Yang et al. describe a protective effect from a low-branched chain amino acid (BCAA) diet in a mouse model of heart failure. The findings implicate a propionylation mark on histone H3 lysine 23 (H3K23Pr), previously shown to be dependent on the BCAA isoleucine, in transcriptional control of the cardiac stress response. The result underscores the interplay between metabolism and histone acylation, highlighting targeted dietary and pharmacological intervention as a means to decelerate cardiac hypertrophy.

DOI: https://doi.org/10.1172/JCI174953
Circulation. 2023 Nov 14.

Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function.

Weiyi Xu, Cyrielle Billon, Hui Li, Andrea Wilderman, Lei Qi, Andrea Graves, Jernie Rae Dela Cruz Rideb, Yuanbiao Zhao, Matthew Hayes, Keyang Yu, McKenna Losby, Carissa S Hampton, Christiana M Adeyemi, Seok Jae Hong, Eleni Nasiotis, Chen Fu, Tae Gyu Oh, Weiwei Fan, Michael Downes, Ryan D Welch, Ronald M Evans, Aleksandar Milosavljevic, John K Walker, Brian C Jensen, Liming Pei, Thomas Burris, Lilei Zhang.

  BACKGROUND: Cardiac metabolic dysfunction is a hallmark of heart failure (HF). Estrogen-related receptors ERRα and ERRγ are essential regulators of cardiac metabolism. Therefore, activation of ERR could be a potential therapeutic intervention for HF. However, in vivo studies demonstrating the potential usefulness of ERR agonist for HF treatment are lacking, because compounds with pharmacokinetics appropriate for in vivo use have not been available.METHODS: Using a structure-based design approach, we designed and synthesized 2 structurally distinct pan-ERR agonists, SLU-PP-332 and SLU-PP-915. We investigated the effect of ERR agonist on cardiac function in a pressure overload-induced HF model in vivo. We conducted comprehensive functional, multi-omics (RNA sequencing and metabolomics studies), and genetic dependency studies both in vivo and in vitro to dissect the molecular mechanism, ERR isoform dependency, and target specificity.
RESULTS: Both SLU-PP-332 and SLU-PP-915 significantly improved ejection fraction, ameliorated fibrosis, and increased survival associated with pressure overload-induced HF without affecting cardiac hypertrophy. A broad spectrum of metabolic genes was transcriptionally activated by ERR agonists, particularly genes involved in fatty acid metabolism and mitochondrial function. Metabolomics analysis showed substantial normalization of metabolic profiles in fatty acid/lipid and tricarboxylic acid/oxidative phosphorylation metabolites in the mouse heart with 6-week pressure overload. ERR agonists increase mitochondria oxidative capacity and fatty acid use in vitro and in vivo. Using both in vitro and in vivo genetic dependency experiments, we show that ERRγ is the main mediator of ERR agonism-induced transcriptional regulation and cardioprotection and definitively demonstrated target specificity. ERR agonism also led to downregulation of cell cycle and development pathways, which was partially mediated by E2F1 in cardiomyocytes.
CONCLUSIONS: ERR agonists maintain oxidative metabolism, which confers cardiac protection against pressure overload-induced HF in vivo. Our results provide direct pharmacologic evidence supporting the further development of ERR agonists as novel HF therapeutics.

Keywords:  cell cycle; heart failure; metabolism

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.066542
BMC Cardiovasc Disord. 2023 Nov 15. 23(1): 557

Effect of empagliflozin on cardiac remodelling in South Asian and non-South Asian individuals: insights from the EMPA-HEART CardioLink-6 randomised clinical trial.

William Barbour, Erika Wolff, Pankaj Puar, Makoto Hibino, Ehab Bakbak, Aishwarya Krishnaraj, Raj Verma, Meena Verma, Adrian Quan, Andrew T Yan, Kim A Connelly, Hwee Teoh, C David Mazer, Subodh Verma.

  BACKGROUND: This exploratory sub-analysis of the EMPA-HEART CardioLink-6 trial examined whether the previously reported benefit of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin on left ventricular (LV) mass (LVM) regression differs between individuals of South Asian and non-South Asian ethnicity.METHODS: EMPA-HEART CardioLink-6 was a double-blind, placebo-controlled clinical trial that randomised 97 individuals with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) to either empagliflozin 10 mg daily or placebo for 6 months. LV parameters and function were assessed using cardiac magnetic resonance imaging. The 6-month changes in LVM and LV volumes, all indexed to baseline body surface area, for South Asian participants were compared to those for non-South Asian individuals.
RESULTS: Compared to the non-South Asian group, the South Asian sub-cohort comprised more males, was younger and had a lower median body mass index. The adjusted difference for LVMi change over 6 months was -4.3 g/m2 (95% confidence interval [CI], -7.5, -1.0; P = 0.042) for the South Asian group and -2.3 g/m2 (95% CI, -6.4, 1.9; P = 0.28) for the non-South Asian group (Pinteraction = 0.45). There was no between-group difference for the adjusted differences in baseline body surface area-indexed LV volumes and LV ejection fraction.
CONCLUSIONS: There was no meaningful difference in empagliflozin-associated LVM regression between South Asian and non-South Asian individuals living with T2DM and CAD in the EMPA-HEART CardioLink-6 trial.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02998970 (First posted on 21/12/ 2016).

Keywords:  Coronary artery disease; Left ventricular mass regression; SGLT2 inhibition; South Asian ethnicity; Type 2 diabetes mellitus

DOI:  https://doi.org/10.1186/s12872-023-03549-5
Reprod Sci. 2023 Nov 13.

Nicotinamide Riboside, an NAD + Precursor, Protects Against Cardiac Mitochondrial Dysfunction in Fetal Guinea Pigs Exposed to Gestational Hypoxia.

Loren P Thompson, Hong Song, Jamie Hartnett.

  Gestational hypoxia inhibits mitochondrial function in the fetal heart and placenta contributing to fetal growth restriction and organ dysfunction. NAD + deficiency may contribute to a metabolic deficit by inhibiting oxidative phosphorylation and ATP synthesis. We tested the effects of nicotinamide riboside (NR), an NAD + precursor, as a treatment for reversing known mitochondrial dysfunction in hypoxic fetal hearts. Pregnant guinea pigs were housed in room air (normoxia) or placed in a hypoxic chamber (10.5%O2) for the last 14 days of gestation (term = 65 days) and administered either water or NR (1.6 mg/ml) in the drinking bottle. Fetuses were excised at term, and NAD + levels of maternal liver, placenta, and fetal heart ventricles were measured. Indices of mitochondrial function (complex IV activity, sirtuin 3 activity, protein acetylation) and ATP synthesis were measured in fetal heart ventricles of NR-treated/untreated normoxic and hypoxic animals. Hypoxia reduced fetal body weight in both sexes (p = 0.01), which was prevented by NR. Hypoxia had no effect on maternal liver NAD + levels but decreased (p = 0.04) placenta NAD + levels, the latter normalized with NR treatment. Hypoxia had no effect on fetal heart NAD + but decreased (p < 0.05) mitochondrial complex IV and sirtuin 3 activities, ATP content, and increased mitochondrial acetylation, which were all normalized with maternal NR. Hypoxia increased (p < 0.05) mitochondrial acetylation in female fetal hearts but had no effect on other mitochondrial indices. We conclude that maternal NR is an effective treatment for normalizing mitochondrial dysfunction and ATP synthesis in the hypoxic fetal heart.

Keywords:  Acetylation; Fetus; Heart; Hypoxia; Mitochondria; NAD; Nicotinamide; Placenta; Sirtuin

DOI:  https://doi.org/10.1007/s43032-023-01387-6
Basic Res Cardiol. 2023 Nov 13. 118(1): 49

Targeting mitochondrial shape: at the heart of cardioprotection.

Sauri Hernandez-Resendiz, Aishwarya Prakash, Sze Jie Loo, Martina Semenzato, Kroekkiat Chinda, Gustavo E Crespo-Avilan, Linh Chi Dam, Shengjie Lu, Luca Scorrano, Derek J Hausenloy.

  There remains an unmet need to identify novel therapeutic strategies capable of protecting the myocardium against the detrimental effects of acute ischemia-reperfusion injury (IRI), to reduce myocardial infarct (MI) size and prevent the onset of heart failure (HF) following acute myocardial infarction (AMI). In this regard, perturbations in mitochondrial morphology with an imbalance in mitochondrial fusion and fission can disrupt mitochondrial metabolism, calcium homeostasis, and reactive oxygen species production, factors which are all known to be critical determinants of cardiomyocyte death following acute myocardial IRI. As such, therapeutic approaches directed at preserving the morphology and functionality of mitochondria may provide an important strategy for cardioprotection. In this article, we provide an overview of the alterations in mitochondrial morphology which occur in response to acute myocardial IRI, and highlight the emerging therapeutic strategies for targeting mitochondrial shape to preserve mitochondrial function which have the future therapeutic potential to improve health outcomes in patients presenting with AMI.

Keywords:  Acute myocardial infarction; Acute myocardial ischemia–reperfusion injury; Cardioprotection; Cardiovascular diseases; Heart failure; Mitochondrial morphology

DOI:  https://doi.org/10.1007/s00395-023-01019-9
J Clin Biochem Nutr. 2023 Nov;73(3): 205-213

Combined fructose and sucrose consumption from an early age aggravates cardiac oxidative damage and causes a dilated cardiomyopathy in SHR rats.

David Julian Arias-Chávez, Patrick Mailloux-Salinas, Jessica Ledesma Aparicio, Guadalupe Bravo, Norma Leticia Gómez-Viquez.

  Obesity increases the risk of arterial hypertension in young adults and favors an early-onset cardiomyopathy by generating oxidative stress. In this sense, indiscriminate consumption of sucrose and fructose sweetened beverages from early ages causes obesity, however its consequences on the heart when there is a genetic predisposition to develop hypertension are not clear. We compared the effects of sucrose, fructose, and their combination in weanling male spontaneously hypertensive rats to determine the relationship between genetic hypertension, obesity, and consumption of these sugars on the degree of cardiac hypertrophy, oxidative stress and Ca2+/calmodulin dependent protein kinase II delta oxidation. Histological, biochemical, and Western blot studies were performed 12 weeks after treatment initiation. We found that chronic consumption of sucrose or fructose leads to obesity, exacerbates genetic arterial hypertension-induced metabolic alterations, and increases cardiac oxidative stress, Ca2+/calmodulin dependent protein kinase II delta oxidation and cardiac hypertrophy. Nonetheless, when sucrose and fructose are consumed together, metabolic alterations worsen and are accompanied by dilated cardiomyopathy. These data suggest that sucrose and fructose combined consumption starting from maternal weaning in rats with genetic predisposition to arterial hypertension accelerates the progression of cardiomyopathy resulting in an early dilated cardiomyopathy.

Keywords:  CaMKIIδ; arterial hypertension; cardiac hypertrophy; dilated cardiomyopathy; high fructose diet; high sucrose diet; oxidative stress

DOI:  https://doi.org/10.3164/jcbn.23-2