bims-hafaim 2022-08-14 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2022–08–14
seven papers selected by
Kyle McCommis, Saint Louis University

Short-Chain Carbon Sources: Exploiting Pleiotropic Effects for Heart Failure Therapy.
Empagliflozin prohibits high-fructose diet-induced cardiac dysfunction in rats via attenuation of mitochondria-driven oxidative stress.
Hyperglycemia promotes myocardial dysfunction via the ERS-MAPK10 signaling pathway in db/db mice.
Palmitate Induces Mitochondrial Energy Metabolism Disorder and Cellular Damage via the PPAR Signaling Pathway in Diabetic Cardiomyopathy.
Investigating the roles of hyperglycaemia, hyperinsulinaemia and elevated free fatty acids in cardiac function in patients with type 2 diabetes via treatment with insulin compared with empagliflozin: protocol for the HyperCarD2 randomised, crossover trial.
Dual specificity phosphatase 1 attenuates inflammation-induced cardiomyopathy by improving mitophagy and mitochondrial metabolism.
αSMA-Cre-mediated Ogt deletion leads to heart failure and vascular smooth muscle cell dysfunction in mice.

JACC Basic Transl Sci. 2022 Jul;7(7): 730-742

Short-Chain Carbon Sources: Exploiting Pleiotropic Effects for Heart Failure Therapy.

Azariyas A Challa, E Douglas Lewandowski.

  Heart failure (HF) remains the leading cause of morbidity and mortality in the developed world, highlighting the urgent need for novel, effective therapeutics. Recent studies support the proposition that improved myocardial energetics as a result of ketone body (KB) oxidation may account for the intriguing beneficial effects of sodium-glucose cotransporter-2 inhibitors in patients with HF. Similar small molecules, short-chain fatty acids (SCFAs) are now realized to be preferentially oxidized over KBs in failing hearts, contradicting the notion of KBs as a rescue "superfuel." In addition to KBs and SCFAs being alternative fuels, both exert a wide array of nonmetabolic functions, including molecular signaling and epigenetics and as effectors of inflammation and immunity, blood pressure regulation, and oxidative stress. In this review, the authors present a perspective supported by new evidence that the metabolic and unique nonmetabolic activities of KBs and SCFAs hold promise for treatment of patients with HF with reduced ejection fraction and those with HF with preserved ejection fraction.

Keywords:  BP, blood pressure; CPT1, carnitine palmitoyltransferase I; CoA, coenzyme A; FFAR, free fatty acid receptor; GPR, G protein–coupled receptor; HF, heart failure; HFpEF; HFpEF, heart failure with preserved ejection fraction; HFrEF; KB, ketone body; LCFA, long-chain fatty acid; SCFA, short-chain fatty acid; SGLT2, sodium-glucose cotransporter-2; heart failure; ketones; short-chain fatty acids; β-HB, β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.jacbts.2021.12.010
Life Sci. 2022 Aug 04. pii: S0024-3205(22)00562-8. [Epub ahead of print] 120862

Empagliflozin prohibits high-fructose diet-induced cardiac dysfunction in rats via attenuation of mitochondria-driven oxidative stress.

Paramesha Bugga, Soheb Anwar Mohammed, Md Jahangir Alam, Parmeshwar Katare, Himanshu Meghwani, Subir Kumar Maulik, Sudheer Arava, Sanjay Kumar Banerjee.

  SGLT2 inhibitors show promising cardio-protection in the diabetic populace. However, the defending effect of SGLT2 inhibition in diabetes-associated cardiac complications and the molecular mechanism behind this effect are not thoroughly studied. Therefore, we aimed to investigate the effect of Empagliflozin, an SGLT2 inhibitor, in type-2 diabetic rat hearts. We induced type-2 diabetes in SD rats by giving a high-fructose diet for 20 weeks. We administered Empagliflozin (10 mg/kg p.o.) daily from the 12th week to the 20th week, along with a high-fructose diet. We weighed the cardiac structure and function by echocardiography, electrocardiography, and blood pressure in diabetic rats. Other parameters like cardiac fibrosis, oxidative stress, and mitochondrial dynamics by protein expression were measured. To simulate a similar in-vivo condition, we persuaded insulin resistance in H9c2 cells by palmitic acid (PA) treatment. We then examined glucose uptake, cellular ROS, mitochondrial ROS and membrane potential in the presence and absence of Empagliflozin treatment. We saw a significant perturbation of the majority of the parameters associated with cardiac structure and function in high-fructose diet-induced diabetic rats. We found that administration of Empagliflozin improved all the perturbed parameters by attenuating insulin resistance, oxidative stress, and cardiac fibrosis and also by promoting cardiac mitochondrial fusion in high-fructose diet-induced type-2 diabetic rats. Empagliflozin also reduced palmitate-induced insulin resistance, total cellular ROS, and mitochondrial ROS in H9c2 cells. Our study concluded that SGLT2 inhibition with Empagliflozin prevented the high-fructose diet-insulted cardiac function by suppressing insulin resistance and oxidative stress and promoting mitochondrial fusion.

Keywords:  Empagliflozin; Insulin resistance; Mitochondrial dysfunction; Oxidative stress; Palmitate

DOI:  https://doi.org/10.1016/j.lfs.2022.120862
Lab Invest. 2022 Aug 08.

Hyperglycemia promotes myocardial dysfunction via the ERS-MAPK10 signaling pathway in db/db mice.

Ya-Wen Deng, Fei Liu, Zhi-Tong Li, Jing-Han Gao, Yong Zhao, Xiao-Lei Yang, Yun-Long Xia.

Recent studies have demonstrated that hyperglycemia is a major risk factor for the development and exacerbation of cardiovascular disease (CVD). However, the molecular mechanisms involved in diabetic cardiomyopathy (DCM) have not been fully elucidated. In this study, we focused on the underlying mechanism of DCM. Leptin receptor-deficient db/db mice were used to model a type 2 diabetes mellitus (T2DM) model in our study. WT mice and db/db mice received 4-phenylbutyric acid (4-PBA) (25 mg/kg/day) and saline by intraperitoneal injection every other day for 4 weeks. WT and db/db mice were given tail vein injections of 100 μL of rAAV9-Sh-MAPK10 and rAAV9-Sh-GFP at the age of 6-8 weeks. Echocardiography was performed to measure cardiac function, histological examinations were used to evaluate ventricular hypertrophy and fibrosis. Quantitative RT-qPCR was used to assess the mRNA expression of Jun N-terminal kinase 3 (JNK3, MAPK10), atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and collagen I and III. Immunoblotting was performed to measure the levels of cardiac hypertrophy-related proteins, fibrosis-related proteins, endoplasmic reticulum stress (ERS)-related proteins and apoptosis-related proteins. TUNEL staining was performed to examine cardiomyocyte apoptosis. In contrast to 12-week-old db/db mice, 16-week-old db/db mice showed the most severe myocardial dysfunction. The DCM induced by hyperglycemia was largely alleviated by 4-PBA (25 mg/kg/day, intraperitoneal injection). Similarly, tail vein injection of rAAV9-Sh-MAPK10 reversed the phenotype of the heart in db/db mice including cardiac hypertrophy and apoptosis in db/db mice. The mechanistic findings suggested that hyperglycemia initiated the ERS response through the negative regulation of sirtuin 1 (SIRT1), leading to the occurrence of myocardial dysfunction, and specific knockdown of MAPK10 in the heart directly reversed myocardial dysfunction induced by hyperglycemia. We demonstrated that hyperglycemia promotes DCM in db/db mice through the ERS-MAPK10 signaling pathway in diabetic mice.

DOI: https://doi.org/10.1038/s41374-022-00819-2
Diabetes Metab Syndr Obes. 2022 ;15 2287-2299

Palmitate Induces Mitochondrial Energy Metabolism Disorder and Cellular Damage via the PPAR Signaling Pathway in Diabetic Cardiomyopathy.

Xianyu Zhang, Min Mao, Zhong Zuo.

   Purpose: To establish an in vitro lipotoxicity model with mouse cardiomyocytes (MCMs) and investigate the molecular mechanism of the peroxisome proliferator-activated receptors (PPAR) signaling on mitochondrial energy metabolism disorder and cellular injury in diabetic cardiomyopathy (DCM).
Methods: Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on the differentially expressed genes (DEGs) of DCM. CCK-8 method was used to detect the proliferation inhibition effect of palmitate (PA) on MCMs. Oil red O staining and mRNA levels of CD36 were used to verify intracellular lipid accumulation. DCFH-DA method was used to determine the content of intracellular reactive oxygen species (ROS), and ATP levels were detected by the ATP Detection Kit. Transmission electron microscope (TEM) was used to observe the mitochondrial structure. Western blot was used to detect the expression levels of PPARα, PPARγ, P-mTOR, mTOR, PGC-1α, UCP2, and BNP. In addition, the expression of PPARγ was also detected by cellular immunofluorescence staining. BNP levels were detected by qRT-PCR and the ELISA Kit.
Results: KEGG pathway analysis combined with GO analysis has shown that PPAR signaling played a significant regulatory role in mitochondrial biogenesis and fatty acid metabolism in DCM. Then, MCMs stimulated with PA for 24 h were selected as an in vitro lipotoxicity model. PA decreased cell viability, cell membrane shrinkage, and lipid accumulation. Meanwhile, PA-induced increase in cellular ROS led to ATP generation reduction and mitochondrial damage. Furthermore, the expression levels of p-mTOR- PPARα/γ were decreased, and the expressions of PGC-1α and UCP2 were increased. The levels of BNP were elevated, demonstrating PA impaired cardiomyocytes.
Conclusion: Mitochondrial energy metabolism obstacle and cell injury appeared in cardiac lipotoxicity of DCM, associated with lipid accumulation and increased ROS, indicating a crosstalk with the PPAR pathway mediated mechanism.

Keywords:  PPAR; cell damage; diabetic cardiomyopathy; lipotoxicity; mitochondrial energy metabolism

DOI:  https://doi.org/10.2147/DMSO.S360931
BMJ Open. 2022 Aug 11. 12(8): e054100

Investigating the roles of hyperglycaemia, hyperinsulinaemia and elevated free fatty acids in cardiac function in patients with type 2 diabetes via treatment with insulin compared with empagliflozin: protocol for the HyperCarD2 randomised, crossover trial.

Roopameera Thirumathyam, Erik Arne Richter, Jens Peter Goetze, Mogens Fenger, Gerrit Van Hall, Ulrik Dixen, Jens Juul Holst, Sten Madsbad, Niels Vejlstrup, Per Lav Madsen, Nils Bruun Jørgensen.

   INTRODUCTION: Type 2 diabetes (T2D) is characterised by elevated plasma glucose, free fatty acid (FFA) and insulin concentrations, and this metabolic profile is linked to diabetic cardiomyopathy, a diastolic dysfunction at first and increased cardiovascular disease (CVD) risk. Shifting cardiac metabolism towards glucose utilisation has been suggested to improve cardiovascular function and CVD risk, but insulin treatment increases overall glucose oxidation and lowers lipid oxidation, without reducing CVD risk, whereas SGLT2 inhibitors (SGLT2i) increase FFA, ketone body concentrations and lipid oxidation, while decreasing insulin concentrations and CVD risk. The aim of the present study is to elucidate the importance of different metabolic profiles obtained during treatment with a SGLT2i versus insulin for myocardial function in patients with T2D.
METHODS AND ANALYSES: Randomised, crossover study, where 20 patients with T2D and body mass index>28 kg/m2 receive 25 mg empagliflozin daily or NPH insulin two times per day first for 5 weeks followed by a 3-week washout before crossing over to the remaining treatment. Insulin treatment is titrated to achieve similar glycaemic control as with empagliflozin. In those randomised to insulin first, glycaemia during an initial empagliflozin run-in period prior to randomisation serves as target glucose. Metabolic and cardiac evaluation is performed before and at the end of each treatment period.The primary endpoint is change (treatment-washout) in left ventricular peak filling rate, as assessed by cardiac MRI with and without acute lowering of plasma FFAs with acipimox. Secondary and explorative endpoints are changes in left atrial passive emptying fraction, left ventricular ejection fraction, central blood volume and metabolic parameters.
ETHICS AND DISSEMINATION: This study is approved by the Danish Medicines Agency (ref. nr.: 2017061587), the Danish Data Protection Agency (ref. nr.: AHH-2017-093) and the Capital Region Ethics Committee (ref. nr.: H-17018846). The trial will be conducted in accordance with ICH-GCP guidelines and the Declaration of Helsinki and all participants will provide oral and written informed consent. Our results, regardless of outcome, will be published in relevant scientific journals and we also will seek to disseminate results through presentations at scientific meetings.
TRIAL REGISTRATION NUMBER: EudraCT: 2017-002101.

Keywords:  coronary heart disease; diabetes & endocrinology; diabetic nephropathy & vascular disease; ischaemic heart disease; myocardial infarction

DOI:  https://doi.org/10.1136/bmjopen-2021-054100
Mol Metab. 2022 Aug 06. pii: S2212-8778(22)00136-3. [Epub ahead of print] 101567

Dual specificity phosphatase 1 attenuates inflammation-induced cardiomyopathy by improving mitophagy and mitochondrial metabolism.

Ying Tan, Yue Zhang, Jing He, Feng Wu, Di Wu, Nengxian Shi, Weifeng Liu, Ziying Li, Wenqian Liu, Hao Zhou, Wenting Chen.

   OBJECTIVES: Dual specificity phosphatase 1 (DUSP1) is regarded as an anti-inflammatory factor in cardiovascular disorders. Mitophagy removes damaged mitochondria and thus promotes mitochondrial regeneration. We investigated whether DUSP1 could attenuate inflammation-induced cardiomyopathy by improving mitophagy.
METHODS: Lipopolysaccharide was used to induce septic cardiomyopathy in wild-type (WT) and DUSP1 transgenic (DUSP1TG) mice.
RESULTS: Echocardiography revealed that lipopolysaccharide impaired heart function by reducing the cardiac systolic and diastolic capacities of WT mice. Freshly isolated single cardiomyocytes from lipopolysaccharide-treated WT mice also exhibited reduced contractile/relaxation parameters. However, DUSP1 overexpression not only maintained the mechanical properties of cardiomyocytes, but also improved heart performance. Lipopolysaccharide upregulated myocardial inflammatory gene transcription and adhesive factor expression, which increased myocardial neutrophil accumulation and cardiomyocyte apoptosis in WT mice. DUSP1 overexpression inhibited the inflammatory response and therefore promoted cardiomyocyte survival. Lipopolysaccharide disrupted mitochondrial respiration and metabolism in WT cardiomyocytes, but DUSP1 overexpression restored mitochondrial metabolism, maintained the mitochondrial membrane potential and inhibited mitochondrial reactive oxygen species production, possibly by increasing FUN14 domain-containing 1 (FUNDC1)-dependent mitophagy. Silencing of FUNDC1 abolished the protective effects of DUSP1 overexpression on cardiomyocytes and their mitochondria following lipopolysaccharide treatment.
CONCLUSION: These results demonstrated that DUSP1 is a novel anti-inflammatory factor that protects against septic cardiomyopathy by improving FUNDC1-induced mitophagy.

Keywords:  DUSP1; FUNDC1; mitochondria; mitophagy; septic cardiomyopathy

DOI:  https://doi.org/10.1016/j.molmet.2022.101567
Biochem Biophys Res Commun. 2022 Jul 31. pii: S0006-291X(22)01089-0. [Epub ahead of print]625 31-37

αSMA-Cre-mediated Ogt deletion leads to heart failure and vascular smooth muscle cell dysfunction in mice.

Xiwen Xiong, Honghui Ma, Jie Ma, Xiulong Wang, Dongxu Li, Lin Xu.

  Dilated cardiomyopathy, a type of heart muscle disease defined by the presence of left ventricular dilatation and contractile dysfunction, is an important cause of sudden cardiac death and heart failure. O-GlcNAcylation is an important post-translational modification of proteins by the addition of O-GlcNAc moieties at serine or threonine residues. Several studies have shown that proper control of O-GlcNAcylation is required for maintaining physiological function of heart by using Ogt (O-GlcNAc transferase) cardiomyocyte-specific knockout mouse models. In this study, we generated a new mouse model (αSMA-Ogt KO) in which Ogt was deleted in both cardiomyocytes and smooth muscle cells by crossing Ogt floxed mice with αSMA-Cre mice. αSMA-Cre-mediated Ogt deletion in mice led to severe postnatal lethality; the survived mice were smaller than control mice, had dilated hearts, and showed observable signs of heart failure. Moreover, the αSMA-Ogt KO heart had more apoptotic cells and fibrosis. The arteries of αSMA-Ogt KO mice exhibited significantly reduced expression of contractile genes and a trend towards arterial stiffness. In conclusion, our data emphasize the importance of OGT in maintaining normal heart function and reveal a novel role of OGT in regulating arterial contractility.

Keywords:  Cardiomyopathy; Heart; Ogt; Vascular smooth muscle cell (VSMC); αSMA-Cre

DOI:  https://doi.org/10.1016/j.bbrc.2022.07.106