bims-hafaim 2021-09-12 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2021‒09‒12
thirteen papers selected by
Kyle McCommis
Saint Louis University

Pyruvate-Driven Oxidative Phosphorylation is Downregulated in Sepsis-Induced Cardiomyopathy: A Study Of Mitochondrial Proteome.
Possible association between diabetic ketoacidosis and use of sodium-glucose co-transporter 2 inhibitor in a 17-year-old youth with type 2 diabetes.
Diabetic Aldehyde Dehydrogenase 2 Mutant (ALDH2*2) Mice Are More Susceptible to Cardiac Ischemic-Reperfusion Injury Due to 4-Hydroxy-2-Nonenal Induced Coronary Endothelial Cell Damage.
The mitochondrial calcium uniporter promotes arrhythmias caused by high-fat diet.
Lactate and Myocadiac Energy Metabolism.
PRMT5 Prevents Dilated Cardiomyopathy via Suppression of Protein O-GlcNAcylation.
Low-dose PCB126 exposure disrupts cardiac metabolism and causes hypertrophy and fibrosis in mice.
β-hydroxybutyrate accumulates in the rat heart during low-flow ischaemia with implications for functional recovery.
Interleukin-18 accelerates cardiac inflammation and dysfunction during ischemia/reperfusion injury by transcriptional activation of CXCL16.
In vivo deep network tracing reveals phosphofructokinase-mediated coordination of biosynthetic pathway activity in the myocardium.
Biomarker profiles in obesity patients and their relation to cardiac dysfunction.
SGLT-2 inhibitors: A step forward in the treatment of heart failure with reduced ejection fraction.
Knock-Out of DHTKD1 Alters Mitochondrial Respiration and Function, and May Represent a Novel Pathway in Cardiometabolic Disease Risk.

Shock. 2021 Sep 09.

Pyruvate-Driven Oxidative Phosphorylation is Downregulated in Sepsis-Induced Cardiomyopathy: A Study Of Mitochondrial Proteome.

Briana K Shimada, Liron Boyman, Weiliang Huang, Jing Zhu, Yang Yang, Fengqian Chen, Maureen A Kane, Nagendra Yadava, Lin Zou, W Jonathan Lederer, Brian M Polster, Wei Chao.

BACKGROUND: Sepsis-induced cardiomyopathy (SIC) is a major contributing factor for morbidity and mortality in sepsis. Accumulative evidence has suggested that cardiac mitochondrial oxidative phosphorylation is attenuated in sepsis, but the underlying molecular mechanisms remain incompletely understood.METHODS: Adult male mice of 9-12 weeks old were subjected to sham or cecal ligation and puncture procedure. Echocardiography in vivo and Langendorff-perfused hearts were used to assess cardiac function 24 hours after the procedures. Unbiased proteomics analysis was performed to profile mitochondrial proteins in the hearts of both sham and SIC mice. Seahorse respirator technology was used to evaluate oxygen consumption in purified mitochondria.
RESULTS: Of the 665 mitochondrial proteins identified in the proteomics assay, 35 were altered in septic mice. The mitochondrial remodeling involved various energy metabolism pathways including subunits of the electron transport chain, fatty acid catabolism, and carbohydrate oxidative metabolism. We also identified a significant increase of pyruvate dehydrogenase (PDH) kinase 4 (PDK4) and inhibition of PDH activity in septic hearts. Furthermore, compared to sham mice, mitochondrial oxygen consumption of septic mice was significantly reduced when pyruvate was provided as a substrate. However, it was unchanged when PDH was bypassed by directly supplying the Complex I substrate NADH, or by using the Complex II substrate succinate, or using Complex IV substrate, or by providing the beta-oxidation substrate palmitoylcarnitine, neither of which require PDH for mitochondrial oxygen consumption.
CONCLUSIONS: These data demonstrate a broad mitochondrial protein remodeling, PDH inactivation and impaired pyruvate-fueled oxidative phosphorylation during SIC, and provide a molecular framework for further exploration.

DOI: https://doi.org/10.1097/SHK.0000000000001858
CMAJ. 2021 Sep 07. 193(35): E1385-E1388

Possible association between diabetic ketoacidosis and use of sodium-glucose co-transporter 2 inhibitor in a 17-year-old youth with type 2 diabetes.

Angela Shamchuk, Manpreet Doulla, Mary Jetha.

DOI: https://doi.org/10.1503/cmaj.202627
J Am Heart Assoc. 2021 Sep 06. e021140

Diabetic Aldehyde Dehydrogenase 2 Mutant (ALDH2*2) Mice Are More Susceptible to Cardiac Ischemic-Reperfusion Injury Due to 4-Hydroxy-2-Nonenal Induced Coronary Endothelial Cell Damage.

Guodong Pan, Bipradas Roy, Suresh Selvaraj Palaniyandi.

  Background Aldehyde dehydrogenase-2 (ALDH2), a mitochondrial enzyme, detoxifies reactive aldehydes such as 4-hydroxy-2-nonenal (4HNE). A highly prevalent E487K mutation in ALDH2 (ALDH2*2) in East Asian people with intrinsic low ALDH2 activity is implicated in diabetic complications. 4HNE-induced cardiomyocyte dysfunction was studied in diabetic cardiac damage; however, coronary endothelial cell (CEC) injury in myocardial ischemia-reperfusion injury (IRI) in diabetic mice has not been studied. Therefore, we hypothesize that the lack of ALDH2 activity exacerbates 4HNE-induced CEC dysfunction which leads to cardiac damage in ALDH2*2 mutant diabetic mice subjected to myocardial IRI. Methods and Results Three weeks after diabetes mellitus (DM) induction, hearts were subjected to IRI either in vivo via left anterior descending artery occlusion and release or ex vivo IRI by using the Langendorff system. The cardiac performance was assessed by conscious echocardiography in mice or by inserting a balloon catheter in the left ventricle in the ex vivo model. Just 3 weeks of DM led to an increase in cardiac 4HNE protein adducts and, cardiac dysfunction, and a decrease in the number of CECs along with reduced myocardial ALDH2 activity in ALDH2*2 mutant diabetic mice compared with their wild-type counterparts. Systemic pretreatment with Alda-1 (10 mg/kg per day), an activator of both ALDH2 and ALDH2*2, led to a reduction in myocardial infarct size and dysfunction, and coronary perfusion pressure upon cardiac IRI by increasing CEC population and coronary arteriole opening. Conclusions Low ALDH2 activity exacerbates 4HNE-mediated CEC injury and thereby cardiac dysfunction in diabetic mouse hearts subjected to IRI, which can be reversed by ALDH2 activation.

Keywords:  4‐hydroxy‐2‐nonenal; Langendorff system; aldehyde dehydrogenase‐2; cardiac dysfunction; coronary endothelial cells; diabetic heart; ischemia‐reperfusion injury

DOI:  https://doi.org/10.1161/JAHA.121.021140
Sci Rep. 2021 Sep 08. 11(1): 17808

The mitochondrial calcium uniporter promotes arrhythmias caused by high-fat diet.

Leroy C Joseph, Michael V Reyes, Edwin A Homan, Blake Gowen, Uma Mahesh R Avula, Chris N Goulbourne, Elaine Y Wan, John W Elrod, John P Morrow.

Obesity and diabetes increase the risk of arrhythmia and sudden cardiac death. However, the molecular mechanisms of arrhythmia caused by metabolic abnormalities are not well understood. We hypothesized that mitochondrial dysfunction caused by high fat diet (HFD) promotes ventricular arrhythmia. Based on our previous work showing that saturated fat causes calcium handling abnormalities in cardiomyocytes, we hypothesized that mitochondrial calcium uptake contributes to HFD-induced mitochondrial dysfunction and arrhythmic events. For experiments, we used mice with conditional cardiac-specific deletion of the mitochondrial calcium uniporter (Mcu), which is required for mitochondrial calcium uptake, and littermate controls. Mice were used for in vivo heart rhythm monitoring, perfused heart experiments, and isolated cardiomyocyte experiments. MCU KO mice are protected from HFD-induced long QT, inducible ventricular tachycardia, and abnormal ventricular repolarization. Abnormal repolarization may be due, at least in part, to a reduction in protein levels of voltage gated potassium channels. Furthermore, isolated cardiomyocytes from MCU KO mice exposed to saturated fat are protected from increased reactive oxygen species (ROS), mitochondrial dysfunction, and abnormal calcium handling. Activation of calmodulin-dependent protein kinase (CaMKII) corresponds with the increase in arrhythmias in vivo. Additional experiments showed that CaMKII inhibition protects cardiomyocytes from the mitochondrial dysfunction caused by saturated fat. Hearts from transgenic CaMKII inhibitor mice were protected from inducible ventricular tachycardia after HFD. These studies identify mitochondrial dysfunction caused by calcium overload as a key mechanism of arrhythmia during HFD. This work indicates that MCU and CaMKII could be therapeutic targets for arrhythmia caused by metabolic abnormalities.

DOI: https://doi.org/10.1038/s41598-021-97449-3
Front Physiol. 2021 ;12 715081

Lactate and Myocadiac Energy Metabolism.

Shuohui Dong, Linhui Qian, Zhiqiang Cheng, Chang Chen, Kexin Wang, Sanyuan Hu, Xiang Zhang, Tongzhi Wu.

  The myocardium is capable of utilizing different energy substrates, which is referred to as "metabolic flexibility." This process assures ATP production from fatty acids, glucose, lactate, amino acids, and ketones, in the face of varying metabolic contexts. In the normal physiological state, the oxidation of fatty acids contributes to approximately 60% of energy required, and the oxidation of other substrates provides the rest. The accumulation of lactate in ischemic and hypoxic tissues has traditionally be considered as a by-product, and of little utility. However, recent evidence suggests that lactate may represent an important fuel for the myocardium during exercise or myocadiac stress. This new paradigm drives increasing interest in understanding its role in cardiac metabolism under both physiological and pathological conditions. In recent years, blood lactate has been regarded as a signal of stress in cardiac disease, linking to prognosis in patients with myocardial ischemia or heart failure. In this review, we discuss the importance of lactate as an energy source and its relevance to the progression and management of heart diseases.

Keywords:  cardiac metabolism; diabetic cardiomyopathy; energy substrate; heart failure; lactate; lactate shuttle theory; myocardial ischemia; myocardium

DOI:  https://doi.org/10.3389/fphys.2021.715081
Circ Res. 2021 Sep 10.

PRMT5 Prevents Dilated Cardiomyopathy via Suppression of Protein O-GlcNAcylation.

Zhenhua Li, Jingping Xu, Yao Song, Chong Xin, Lantao Liu, Ning Hou, Yan Teng, Xuan Cheng, Tianle Wang, Zhenyang Yu, Jiangping Song, You-Yi Zhang, Jian Wang, Xiao Yang.

Rationale: Protein O-GlcNAcylation is dynamically regulated by two key enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Excessive protein O-GlcNAcylation contributes to dilated cardiomyopathy (DCM), but its regulatory mechanisms are not fully understood. The protein arginine methyltransferase 5 (PRMT5) is the major type II arginine methyltransferase, which plays critical physiological roles by symmetrically dimethylating various downstream targets including proteins involved in RNA splicing. However, its function in regulating protein O-GlcNAcylation and DCM is unexplored. Objective: To elucidate the physiological function of PRMT5 and the mechanism underlying its role in regulating cardiac O-GlcNAcylation and homeostasis. Methods and Results: Conditional gene knockout was used to study the in vivo function of Prmt5 in regulating cardiac homeostasis. An integrated analysis of transcriptomic and metabolomic profiles was performed to investigate the molecular mechanism. Adeno-associated virus 9 (AAV9)-mediated gene delivery in the mouse was used to study the protein O-GlcNAcylation in Prmt5 deficiency-induced DCM. PRMT5 mRNA was decreased in human DCM hearts, and cardiomyocyte-specific Prmt5 deletion in mice resulted in DCM and heart failure. Transcriptomic and metabolomic profiling identified increased O-GlcNAcylation in the hearts of Prmt5-knockout mice. Mechanistically, Prmt5 deletion suppressed O-GlcNAcase (OGA) expression by inhibiting the transcription of Oga and triggering its aberrant splicing. Consistently, a positive correlation of PRMT5 and OGA was identified in human DCM hearts. Notably, gene therapy with AAV9 encoding the correctly spliced Oga normalized the cardiac protein O-GlcNAcylation levels and partially rescued the dilation and dysfunction of the hearts in Prmt5-knockout mice. Conclusions: Our data demonstrate a novel function of PRMT5 in regulating protein O-GlcNAcylation to maintain cardiac homeostasis, suggesting that targeting the PRMT5-OGA axis could be a potential strategy for treating DCM.

DOI: https://doi.org/10.1161/CIRCRESAHA.121.319456
Environ Pollut. 2021 Aug 31. pii: S0269-7491(21)01661-4. [Epub ahead of print]290 118079

Low-dose PCB126 exposure disrupts cardiac metabolism and causes hypertrophy and fibrosis in mice.

Can Wang, Ruina Cui, Congying Niu, Xiali Zhong, Qicheng Zhu, Di Ji, Xianjie Li, Hongxia Zhang, Chunqiao Liu, Lina Zhou, Yanli Li, Guowang Xu, Yanhong Wei.

  The residue of polychlorinated biphenyls (PCBs) exists throughout the environment and humans are subject to long-term exposure. As such, the potential environmental and health risk caused by low-dose exposure to PCBs has attracted much attention. 3, 3', 4, 4', 5-pentachlorobiphenyl (PCB126), the highest toxicity compound among dioxin-like-PCBs, has been widely used and mass-produced. Cardiotoxicity is PCB126's crucial adverse effect. Maintaining proper metabolism underlies heart health, whereas the impact of PCB126 exposure on cardiac metabolic patterns has yet to be elucidated. In this study, we administered 0.5 and 50 μg/kg bw of PCB126 to adult male mice weekly by gavage for eight weeks. Pathological results showed that low-dose PCB126 exposure induced heart injury. Metabolomic analysis of the heart tissue exposed to low-dose PCB126 identified 59 differential metabolites that were involved in lipid metabolism, amino acid metabolism, and the tricarboxylic acid (TCA) cycle. Typical metabolomic characteristic of cardiac hypertrophy was reflected by accumulation of fatty acids (e.g. palmitic, palmitoleic, and linoleic acid), and disturbance of carbohydrates including D-glucose and intermediates in TCA cycle (fumaric, succinic, and citric acid). Low-dose PCB126 exposure increased glycine and threonine, the amino acids necessary for the productions of collagen and elastin. Besides, PCB126-exposed mice exhibited upregulation of collagen synthesis enzymes and extracellular matrix proteins, indicative of cardiac fibrosis. Moreover, the expression of genes related to TGFβ/PPARγ/MMP-2 signaling pathway was perturbed in the PCB126-treated hearts. Together, our results reveal that low-dose PCB126 exposure disrupts cardiac metabolism correlated with hypertrophy and fibrosis. This study sheds light on the underlying mechanism of PCBs' cardiotoxicity and identifies potential sensitive biomarkers for environmental monitoring.

Keywords:  Cardiotoxicity; Metabolic disturbance; Metabolomics; Polychlorinated biphenyls

DOI:  https://doi.org/10.1016/j.envpol.2021.118079
Elife. 2021 09 07. pii: e71270. [Epub ahead of print]10

β-hydroxybutyrate accumulates in the rat heart during low-flow ischaemia with implications for functional recovery.

Ross T Lindsay, Sophie Dieckmann, Dominika Krzyzanska, Dominic Manetta-Jones, James A West, Cecilia Castro, Julian L Griffin, Andrew J Murray.

  Extrahepatic tissues which oxidise ketone bodies also have the capacity to accumulate them under particular conditions. We hypothesised that acetyl-coenzyme A (acetyl-CoA) accumulation and altered redox status during low-flow ischaemia would support ketone body production in the heart. Combining a Langendorff heart model of low-flow ischaemia/reperfusion with liquid chromatography coupled tandem mass spectrometry (LC-MS/MS), we show that β-hydroxybutyrate (β-OHB) accumulated in the ischaemic heart to 23.9 nmol/gww and was secreted into the coronary effluent. Sodium oxamate, a lactate dehydrogenase (LDH) inhibitor, increased ischaemic β-OHB levels 5.3-fold and slowed contractile recovery. Inhibition of β-hydroxy-β-methylglutaryl (HMG)-CoA synthase (HMGCS2) with hymeglusin lowered ischaemic β-OHB accumulation by 40%, despite increased flux through succinyl-CoA-3-oxaloacid CoA transferase (SCOT), resulting in greater contractile recovery. Hymeglusin also protected cardiac mitochondrial respiratory capacity during ischaemia/reperfusion. In conclusion, net ketone generation occurs in the heart under conditions of low-flow ischaemia. The process is driven by flux through both HMGCS2 and SCOT, and impacts on cardiac functional recovery from ischaemia/reperfusion.

Keywords:  Heart; Ischaemia; Langendorff; biochemistry; cardiomyocyte; cell biology; chemical biology; rat

DOI:  https://doi.org/10.7554/eLife.71270
Cell Signal. 2021 Sep 03. pii: S0898-6568(21)00230-8. [Epub ahead of print] 110141

Interleukin-18 accelerates cardiac inflammation and dysfunction during ischemia/reperfusion injury by transcriptional activation of CXCL16.

Gang Zhao, Hongqiang Zhang, Shijie Zhu, Shijun Wang, Kai Zhu, Yun Zhao, Lei Xu, Ping Zhang, Jing Xie, Aijun Sun, Yunzeng Zou, Junbo Ge.

  Myocardial ischemia/reperfusion(I/R) injury elicits an inflammatory response that drives tissue damage and cardiac remodeling. The trafficking and recruitment of inflammatory cells are controlled by C-X-C motif chemokine ligands and their receptors. CXCL16, a hallmark of acute coronary syndromes, is responsible for the recruitment of macrophages, monocytes and T lymphocytes. However, its role in cardiac I/R injury remains poorly characterized. Here we reported that CXCL16-mediated cardiac infiltration of CD11b+Ly6C+ cells played a crucial role in IL-18-induced myocardial inflammation, apoptosis and left ventricular(LV) dysfunction during I/R. Treatment with CXCL16 shRNA attenuated I/R-induced cardiac injury, LV remodeling and cardiac inflammation by reducing the recruitment of inflammatory cells and the release of TNFα, IL-17 and IFN-γ in the heart. We found that I/R-mediated NLRP3/IL-18 signaling pathway triggered CXCL16 transcription in cardiac vascular endothelial cells(VECs). Two binding sites of FOXO3 were found at the promoter region of CXCL16. By luciferase report assay and ChIP analysis, we confirmed that FOXO3 was responsible for endothelial CXCL16 transcription. A pronounced reduction of CXCL16 was observed in FOXO3 siRNA pretreated-VECs. Further experiments revealed that IL-18 activated FOXO3 by promoting the phosphorylation of STAT3 but not STAT4. An interaction between FOXO3 and STAT3 enhanced the transcription of CXCL16 induced by FOXO3. Treatment with Anakinra or Stattic either effectively inhibited IL-18-mediated nuclear import of FOXO3 and CXCL16 transcription. Our findings suggested that IL-18 accelerated I/R-induced cardiac damage and dysfunction through activating CXCL-16 and CXCL16-mediated cardiac infiltration of the CD11b+Ly6C+ cells. CXCL16 might be a novel therapeutic target for the treatment of I/R-related ischemic heart diseases.

Keywords:  CXCL16; FOXO3; IL-18; Ischemia/reperfusion; NLRP3

DOI:  https://doi.org/10.1016/j.cellsig.2021.110141
J Mol Cell Cardiol. 2021 Sep 03. pii: S0022-2828(21)00172-3. [Epub ahead of print]

In vivo deep network tracing reveals phosphofructokinase-mediated coordination of biosynthetic pathway activity in the myocardium.

Kyle L Fulghum, Timothy N Audam, Pawel K Lorkiewicz, Yuting Zheng, Michael Merchant, Timothy D Cummins, William L Dean, Teresa A Cassel, Teresa W M Fan, Bradford G Hill.

  Glucose metabolism comprises numerous amphibolic metabolites that provide precursors for not only the synthesis of cellular building blocks but also for ATP production. In this study, we tested how phosphofructokinase-1 (PFK1) activity controls the fate of glucose-derived carbon in murine hearts in vivo. PFK1 activity was regulated by cardiac-specific overexpression of kinase- or phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase transgenes in mice (termed GlycoLo or GlycoHi mice, respectively). Dietary delivery of 13C6-glucose to these mice, followed by deep network metabolic tracing, revealed that low rates of PFK1 activity promote selective routing of glucose-derived carbon to the purine synthesis pathway to form 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). Consistent with a mechanism of physical channeling, we found multimeric protein complexes that contained phosphoribosylaminoimidazole carboxylase (PAICS)-an enzyme important for AICAR biosynthesis, as well as chaperone proteins such as Hsp90 and other metabolic enzymes. We also observed that PFK1 influenced glucose-derived carbon deposition in glycogen, but did not affect hexosamine biosynthetic pathway activity. These studies demonstrate the utility of deep network tracing to identify metabolic channeling and changes in biosynthetic pathway activity in the heart in vivo and present new potential mechanisms by which metabolic branchpoint reactions modulate biosynthetic pathways.

Keywords:  Anabolism; Channeling; Glycolysis; Metabolomics; Metabolons; Stable isotope

DOI:  https://doi.org/10.1016/j.yjmcc.2021.08.013
Biomark Med. 2021 Sep 09.

Biomarker profiles in obesity patients and their relation to cardiac dysfunction.

Sanne M Snelder, Nadine Pouw, Yaar Aga, Manuel C Cabezas, Felix Zijlstra, Isabella Kardys, Bas M van Dalen.

  Aim: Current knowledge on the role of obesity in causing cardiac dysfunction is insufficient. Several biomarkers reflecting biological processes that may play a role in the occurrence of cardiac dysfunction in obesity patients are available. Purpose: To compare cardiovascular biomarker profiles between obesity patients and nonobese controls, and between obesity patients with and without cardiac dysfunction, in order to better understand the underlying pathophysiology of cardiac dysfunction in obesity patients. Materials & methods: Blood samples were obtained from 100 obesity patients (BMI ≥35 kg/m2) without known cardiovascular disease, and from 50 age- and gender-matched nonobese controls (BMI ≤30 kg/m2). The third cardiovascular panel of the Olink Multiplex platform was used for the measurement of 92 biomarkers. Results: The majority (53%) of biomarkers were elevated in obesity patients compared with nonobese controls. Only 5% of the biomarkers were elevated in obesity patients with cardiac dysfunction compared with those without. Biomarkers discriminating cardiac dysfunction from no cardiac dysfunction in obesity patients differed from those discriminating obese from nonobese patients. An elastic net model for the prediction of cardiac dysfunction in obesity patients had a high area under the receiver operating curve of 0.87 (95% CI: 0.79-0.94; p < 0.001). The sensitivity of this model was 84% and the specificity was 79%. Conclusion: A multiplex immunoassay was used for the first time in obesity patients without known cardiovascular disease. These patients have cardiovascular biomarker profiles that are clearly different from nonobese controls. Comparison of obesity patients with and without cardiac dysfunction suggested an important role for inflammation, atherosclerosis and insulin resistance in the underlying pathophysiology of cardiac dysfunction in obesity patients.

Keywords:  atherosclerosis; biomarkers; cardiac dysfunction; inflammation; insulin resistance; obesity/obese

DOI:  https://doi.org/10.2217/bmm-2021-0101
Rev Port Cardiol (Engl Ed). 2021 Sep;pii: S2174-2049(21)00251-8. [Epub ahead of print]40(9): 687-693

SGLT-2 inhibitors: A step forward in the treatment of heart failure with reduced ejection fraction.

José Silva-Cardoso, Aurora Andrade, Dulce Brito, Jorge Ferreira, Cândida Fonseca, Marisa Peres, Fátima Franco, Brenda Moura.

  Heart failure (HF) is a major health problem with a significant impact on morbidity, mortality, quality of life and healthcare costs. Despite the positive impact of disease-modifying therapies developed over the last four decades, HF mortality and hospitalization remain high. We aim at reviewing the evidence supporting the use of sodium-glucose co-transporter-2 (SGLT-2) inhibitors, as a novel strategy for HF with reduced ejection fraction (HFrEF) treatment. The consistent observation of a reduction in HF hospitalizations in type-2 diabetes cardiovascular safety trials EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58 and VERTIS raised the hypothesis that SGLT-2 inhibitors could have an impact in HF treatment. This hypothesis was first confirmed in 2019 with the DAPA-HF publication showing that dapagliflozin on top of optimized HFrEF therapy, reduced HF-hospitalizations and cardiovascular mortality. This was reinforced by the EMPEROR-Reduced publication in 2020 showing that empagliflozin on top of optimized HFrEF therapy, reduced HF-hospitalizations. Both studies established SGLT-2 inhibitors as a fourth pillar of HFrEF prognosis-modifying therapy, in addition to the gold standard triple neurohormonal modulation/blockade.

Keywords:  Canagliflozin; Canagliflozina; Cardiovascular mortality; Dapagliflozin; Dapagliflozina; Diabetes mellitus tipo 2; Empagliflozin; Empagliflozina; Ertugliflozin; Ertugliflozina; Heart failure; Heart failure hospitalization; Hospitalização por insuficiência cardíaca; Inibidores do SGLT-2; Insuficiência cardíaca; Mortalidade cardiovascular; SGLT-2 inhibitors; Sotagliflozin; Sotagliflozina; Type-2 diabetes mellitus

DOI:  https://doi.org/10.1016/j.repce.2021.02.006
Front Endocrinol (Lausanne). 2021 ;12 710698

Knock-Out of DHTKD1 Alters Mitochondrial Respiration and Function, and May Represent a Novel Pathway in Cardiometabolic Disease Risk.

Chuan Wang, M Wade Calcutt, Jane F Ferguson.

  Cardiometabolic disease affects the majority of individuals worldwide. The metabolite α-aminoadipic acid (2-AAA) was identified as a biomarker of Type 2 Diabetes (T2D). However, the mechanisms underlying this association remain unknown. DHTKD1, a central gene in the 2-AAA pathway, has been linked to 2-AAA levels and metabolic phenotypes. However, relatively little is known about its function. Here we report that DHTKD1 knock-out (KO) in HAP-1 cells leads to impaired mitochondrial structure and function. Despite impaired mitochondrial respiration and less ATP production, normal cell proliferation rate is maintained, potentially through a series of compensatory mechanisms, including increased mitochondrial content and Akt activation, p38, and ERK signaling. Common variants in DHTKD1 associate with Type 2 Diabetes and cardiometabolic traits in large genome-wide associations studies. These findings highlight the vital role of DHTKD1 in cellular metabolism and establish DHTKD1-mediated mitochondrial dysfunction as a potential novel pathway in cardiometabolic disease.

Keywords:  DHTKD1; Type 2 Diabetes; alpha-aminoadipic acid; cardiometabolic disease; metabolite; mitochondrion; respiration

DOI:  https://doi.org/10.3389/fendo.2021.710698