bims-hafaim 2022-02-20 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2022‒02‒20
six papers selected by
Kyle McCommis
Saint Louis University

Elevated MCU Expression by CaMKIIδB Limits Pathological Cardiac Remodeling.
Myeloid differential protein-2 inhibition improves diabetic cardiomyopathy via p38MAPK inhibition and AMPK pathway activation.
Metabolites and Genes behind Cardiac Metabolic Remodeling in Mice with Type 1 Diabetes Mellitus.
GSK-3β Localizes to the Cardiac Z-Disc to Maintain Length Dependent Activation.
Ketone body oxidation increases cardiac endothelial cell proliferation.
Expression of Iron Metabolism Proteins in Patients with Chronic Heart Failure.

Circulation. 2022 Feb 15.

Elevated MCU Expression by CaMKIIδB Limits Pathological Cardiac Remodeling.

Pei Wang, Shangcheng Xu, Jiqian Xu, Yanguo Xin, Yan Lu, Huiliang Zhang, Bo Zhou, Haodong Xu, Shey-Shing Sheu, Rong Tian, Wang Wang.

Background: Calcium (Ca2+) is a key regulator of energy metabolism. Impaired Ca2+ homeostasis damages mitochondria, causing cardiomyocyte death, pathological hypertrophy, and heart failure. This study investigates the regulation and the role of the mitochondrial Ca2+ uniporter (MCU) in chronic stress-induced pathological cardiac remodeling. Methods: MCU knockout or transgenic mice were infused with isoproterenol (ISO, 10 mg/kg/day, 4 weeks). Cardiac hypertrophy and remodeling were evaluated by echocardiography and histology. Primary cultured rodent adult cardiomyocytes were treated with ISO (1 nM, 48 hr). Intracellular Ca2+ handling and cell death pathways were monitored. Adenovirus-mediated gene manipulations were used in vitro. Results: Chronic administration of the β-adrenergic receptor (β-AR) agonist ISO increased the levels of the MCU and the MCU complex in cardiac mitochondria, raising mitochondrial Ca2+ concentrations, in vivo and in vitro. ISO also upregulated MCU without affecting its regulatory proteins in adult cardiomyocytes. Interestingly, ISO-induced cardiac hypertrophy, fibrosis, contractile dysfunction, and cardiomyocyte death were exacerbated in global MCU knockout (KO) mice. Cardiomyocytes from KO mice or mice overexpressing a dominant negative MCU exhibited defective intracellular Ca2+ handling and activation of multiple cell death pathways. Conversely, cardiac-specific overexpression of MCU maintained intracellular Ca2+ homeostasis and contractility, suppressed cell death, and prevented ISO-induced heart hypertrophy. ISO upregulated MCU expression through activation of Ca2+/calmodulin kinase II δB (CaMKIIδB) and promotion of its nuclear translocation via calcineurin-mediated dephosphorylation at serine 332. Nuclear CaMKIIδB phosphorylated cAMP-response element binding protein (CREB), which bound the MCU promotor to enhance MCU gene transcription. Conclusions: The β-AR/CaMKIIδB/CREB pathway upregulates MCU gene expression in the heart. MCU upregulation is a compensatory mechanism that counteracts stress-induced pathological cardiac remodeling by preserving Ca2+ homeostasis and cardiomyocyte viability.

DOI: https://doi.org/10.1161/CIRCULATIONAHA.121.055841
Biochim Biophys Acta Mol Basis Dis. 2022 Feb 14. pii: S0925-4439(22)00032-1. [Epub ahead of print] 166369

Myeloid differential protein-2 inhibition improves diabetic cardiomyopathy via p38MAPK inhibition and AMPK pathway activation.

Jianchang Qian, Fei Zhuang, Yujing Chen, Xinrong Fan, Jun Wang, Zhe Wang, Yi Wang, Mingjiang Xu, Aleksandr V Samorodov, Valentin N Pavlov, Guang Liang.

  Myeloid differential protein-2 (MD2) has been shown to play a critical role in the progression of diabetic cardiomyopathy (DCM). This study aims to explore the non-inflammatory mechanisms mediated by MD2 in DCM and to test the therapeutic effects of MD2 inhibitor C30 on DCM. Streptozotocin (STZ) was used to construct DCM model in wild-type and MD2 knockout mice. The collected heart samples were subjected to RNA-sequencing assay. Gene set enrichment analysis of the RNA-seq data indicated that MD2 knockout was associated with energy metabolism pathways in diabetic mouse heart. Further data showed that AMPK pathway was impaired under high glucose condition, which was mediated by p38MAPK activation. MD2 knockout or pharmacological inhibitor C30 completely rescued AMPK signaling through p38MAPK inhibition. Importantly, C30 treatment significantly prevented myocardial damage and dysfunction in T1DM mice evidenced by improved cardiac function and reduced cardiomyocyte apoptosis and cardiac fibrosis. Furthermore, the therapeutic effect of C30 on DCM was correlated to p38MAPK inhibition and AMPK pathway activation in vivo and in vitro. In conclusion, MD2 inhibition exhibits therapeutic effects on DCM through p38MAPK inhibition and AMPK activation, which enables MD2 a promising target for DCM treatment by suppressing metaflammation and improving cardiac metabolism.

Keywords:  AMPK; Chalcone; Diabetic cardiomyopathy; Differentiation protein 2; P38MAPK

DOI:  https://doi.org/10.1016/j.bbadis.2022.166369
Int J Mol Sci. 2022 Jan 26. pii: 1392. [Epub ahead of print]23(3):

Metabolites and Genes behind Cardiac Metabolic Remodeling in Mice with Type 1 Diabetes Mellitus.

Tyler N Kambis, Hamid R Shahshahan, Paras K Mishra.

  Metabolic remodeling is at the heart of diabetic cardiomyopathy. High glycemic fluctuations increase metabolic stress in the type 1 diabetes mellitus (T1DM) heart. There is a lack of understanding on how metabolites and genes affect metabolic remodeling in the T1DM heart. We hypothesize that differential expression of metabolic genes and metabolites synergistically influence metabolic remodeling preceding T1DM cardiomyopathy. To test our hypothesis, we conducted high throughput analysis of hearts from adult male hyperglycemic Ins2+/- (Akita) and littermate normoglycemic Ins2+/+ (WT) mice. The Akita mouse is a spontaneous, genetic model of T1DM that develops increased levels of consistent glycemic variability without the off-target cardiotoxic effects present in chemically- induced models of T1DM. After validating the presence of a T1DM phenotype, we conducted metabolomics via LC-MS analysis and genomics via next-generation sequencing in left ventricle tissue from the Akita heart. Ingenuity Pathway Analyses revealed that 108 and 30 metabolic pathways were disrupted within the metabolomics and genomics datasets, respectively. Notably, a comparison between the two analyses showed 15 commonly disrupted pathways, including ketogenesis, ketolysis, cholesterol biosynthesis, acetyl CoA hydrolysis, and fatty acid biosynthesis and beta-oxidation. These identified metabolic pathways predicted by the differential expression of metabolites and genes provide the foundation for understanding metabolic remodeling in the T1DM heart. By limited experiment, we revealed a predicted disruption in the metabolites and genes behind T1DM cardiac metabolic derangement. Future studies targeting these genes and metabolites will unravel novel therapies to prevent/improve metabolic remodeling in the T1DM heart.

Keywords:  TCA cycle; beta-oxidation; diabetic cardiomyopathy; fatty acid; genomics; ketogenesis; ketolysis; metabolomics; next generation sequencing

DOI:  https://doi.org/10.3390/ijms23031392
Circ Res. 2022 Feb 16. CIRCRESAHA121319491

GSK-3β Localizes to the Cardiac Z-Disc to Maintain Length Dependent Activation.

Marisa J Stachowski-Doll, Maria Papadaki, Thomas G Martin, Weikang Ma, Henry M Gong, Stephanie Shao, Shi Shen, Nitha Aima Muntu, Mohit Kumar, Edith Perez, Jody L Martin, Christine S Moravec, Sakthivel Sadayappan, Stuart G Campbell, Thomas Irving, Jonathan A Kirk.

  BACKGROUND: Altered kinase localization is gaining appreciation as a mechanism of cardiovascular disease. Previous work suggests GSK-3β (glycogen synthase kinase 3β) localizes to and regulates contractile function of the myofilament. We aimed to discover GSK-3β's in vivo role in regulating myofilament function, the mechanisms involved, and the translational relevance.METHODS: Inducible cardiomyocyte-specific GSK-3β knockout mice and left ventricular myocardium from nonfailing and failing human hearts were studied.
RESULTS: Skinned cardiomyocytes from knockout mice failed to exhibit calcium sensitization with stretch indicating a loss of length-dependent activation (LDA), the mechanism underlying the Frank-Starling Law. Titin acts as a length sensor for LDA, and knockout mice had decreased titin stiffness compared with control mice, explaining the lack of LDA. Knockout mice exhibited no changes in titin isoforms, titin phosphorylation, or other thin filament phosphorylation sites known to affect passive tension or LDA. Mass spectrometry identified several z-disc proteins as myofilament phospho-substrates of GSK-3β. Agreeing with the localization of its targets, GSK-3β that is phosphorylated at Y216 binds to the z-disc. We showed pY216 was necessary and sufficient for z-disc binding using adenoviruses for wild-type, Y216F, and Y216E GSK-3β in neonatal rat ventricular cardiomyocytes. One of GSK-3β's z-disc targets, abLIM-1 (actin-binding LIM protein 1), binds to the z-disc domains of titin that are important for maintaining passive tension. Genetic knockdown of abLIM-1 via siRNA in human engineered heart tissues resulted in enhancement of LDA, indicating abLIM-1 may act as a negative regulator that is modulated by GSK-3β. Last, GSK-3β myofilament localization was reduced in left ventricular myocardium from failing human hearts, which correlated with depressed LDA.
CONCLUSIONS: We identified a novel mechanism by which GSK-3β localizes to the myofilament to modulate LDA. Importantly, z-disc GSK-3β levels were reduced in patients with heart failure, indicating z-disc localized GSK-3β is a possible therapeutic target to restore the Frank-Starling mechanism in patients with heart failure.

Keywords:  animals; calcium; connectin; myofibrils; rats

DOI:  https://doi.org/10.1161/CIRCRESAHA.121.319491
EMBO Mol Med. 2022 Feb 18. e14753

Ketone body oxidation increases cardiac endothelial cell proliferation.

Eva-Maria Weis, Patrycja Puchalska, Alisa B Nelson, Jacqueline Taylor, Iris Moll, Sana S Hasan, Matthias Dewenter, Marco Hagenmüller, Thomas Fleming, Gernot Poschet, Agnes Hotz-Wagenblatt, Johannes Backs, Peter A Crawford, Andreas Fischer.

  Blood vessel formation is dependent on metabolic adaption in endothelial cells. Glucose and fatty acids are essential substrates for ATP and biomass production; however, the metabolism of other substrates remains poorly understood. Ketone bodies are important nutrients for cardiomyocytes during starvation or consumption of carbohydrate-restrictive diets. This raises the question whether cardiac endothelial cells would not only transport ketone bodies but also consume some of these to achieve their metabolic needs. Here, we report that cardiac endothelial cells are able to oxidize ketone bodies and that this enhances cell proliferation, migration, and vessel sprouting. Mechanistically, this requires succinyl-CoA:3-oxoacid-CoA transferase, a key enzyme of ketone body oxidation. Targeted metabolite profiling revealed that carbon from ketone bodies got incorporated into tricarboxylic acid cycle intermediates as well as other metabolites fueling biomass production. Elevation of ketone body levels by a high-fat, low-carbohydrate ketogenic diet transiently increased endothelial cell proliferation in mouse hearts. Notably, in a mouse model of heart hypertrophy, ketogenic diet prevented blood vessel rarefication. This suggests a potential beneficial role of dietary intervention in heart diseases.

Keywords:  angiogenesis; endothelial cell; heart; ketogenic diet; ketone bodies

DOI:  https://doi.org/10.15252/emmm.202114753
J Clin Med. 2022 Feb 05. pii: 837. [Epub ahead of print]11(3):

Expression of Iron Metabolism Proteins in Patients with Chronic Heart Failure.

Bogna Kozłowska, Barbara Sochanowicz, Leszek Kraj, Małgorzata Palusińska, Piotr Kołsut, Łukasz Szymański, Sławomir Lewicki, Witold Śmigielski, Marcin Kruszewski, Przemysław Leszek.

  In heart failure, iron deficiency is a common comorbid disease that negatively influences exercise tolerance, number of hospitalizations and mortality rate, and this is why iron iv supplementation is recommended. Little is known about the changes in iron-related proteins in the human HF myocardium. The purpose of this study was to assess iron-related proteins in non-failing (NFH) vs. failing (FH) human myocardium. The study group consisted of 58 explanted FHs; control consisted of 31 NFHs unsuitable for transplantation. Myocardial proteins expressions: divalent metal transporter (DMT-1); L-type calcium channel (L-CH); transferrin receptors (TfR-1/TfR-2); ferritins: heavy (FT-H) or light (FT-L) chain, mitochondrial (FT-MT); ferroportin (FPN), regulatory factors and oxidative stress marker: 4-hydroxynonenal (4-HNE). In FH, the expression in almost all proteins responsible for iron transport: DMT-1, TfR-1, L-CH, except TfR-2, and storage: FT-H/-L/-MT were reduced, with no changes in FPN. Moreover, 4-HNE expression (pg/mg; NFH 10.6 ± 8.4 vs. FH 55.7 ± 33.7; p < 0.0001) in FH was increased. HNE-4 significantly correlated with DMT-1 (r = -0.377, p = 0.036), L-CH (r = -0.571, p = 0.001), FT-H (r = -0.379, p = 0.036), also FPN (r = 0.422, p = 0.018). Reducing iron-gathering proteins and elevated oxidative stress in failing hearts is very unfavorable for myocardiocytes. It should be taken into consideration before treatment with drugs or supplements that elevate free oxygen radicals in the heart.

Keywords:  heart failure; human model; myocardial gathering proteins expression; myocardial iron metabolism; oxidative stress

DOI:  https://doi.org/10.3390/jcm11030837