scholarly journals Ketogenic diets inhibit mitochondrial biogenesis and induce cardiac fibrosis

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Sha Xu ◽  
Hui Tao ◽  
Wei Cao ◽  
Li Cao ◽  
Yan Lin ◽  
...  
Keyword(s):  
Mitochondrial Biogenesis ◽  
Ketone Body ◽  
Cardiac Fibrosis ◽  
Cardiomyocyte Apoptosis ◽  
Healthy Individuals ◽  
Cell Respiration ◽  
Ketogenic Diets ◽  
Mitochondrial Ribosome ◽  
Encoding Genes ◽  
Human Atrial Fibrillation

AbstractIn addition to their use in relieving the symptoms of various diseases, ketogenic diets (KDs) have also been adopted by healthy individuals to prevent being overweight. Herein, we reported that prolonged KD exposure induced cardiac fibrosis. In rats, KD or frequent deep fasting decreased mitochondrial biogenesis, reduced cell respiration, and increased cardiomyocyte apoptosis and cardiac fibrosis. Mechanistically, increased levels of the ketone body β-hydroxybutyrate (β-OHB), an HDAC2 inhibitor, promoted histone acetylation of the Sirt7 promoter and activated Sirt7 transcription. This in turn inhibited the transcription of mitochondrial ribosome-encoding genes and mitochondrial biogenesis, leading to cardiomyocyte apoptosis and cardiac fibrosis. Exogenous β-OHB administration mimicked the effects of a KD in rats. Notably, increased β-OHB levels and SIRT7 expression, decreased mitochondrial biogenesis, and increased cardiac fibrosis were detected in human atrial fibrillation heart tissues. Our results highlighted the unknown detrimental effects of KDs and provided insights into strategies for preventing cardiac fibrosis in patients for whom KDs are medically necessary.

scholarly journals Human trophoblast-derived exosomes attenuate doxorubicin-induced cardiac injury by regulating miR-200b and downstream Zeb1

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Jie Ni ◽  
Yihai Liu ◽  
Lina Kang ◽  
Lian Wang ◽  
Zhonglin Han ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Fibrosis ◽  
Cardiac Injury ◽  
Cardiomyocyte Apoptosis ◽  
Luciferase Reporter ◽  
Human Trophoblast ◽  
Trophoblast Stem

AbstractHuman trophoblast stem cells (TSCs) have been confirmed to play a cardioprotective role in heart failure. However, whether trophoblast stem cell-derived exosomes (TSC-Exos) can protect cardiomyocytes from doxorubicin (Dox)-induced injury remains unclear. In the present study, TSC-Exos were isolated from the supernatants of human trophoblasts using the ultracentrifugation method and characterized by transmission electron microscopy and western blotting. In vitro, primary cardiomyocytes were subjected to Dox and treated with TSC-Exos, miR-200b mimic or miR-200b inhibitor. Cellular apoptosis was observed by flow cytometry and immunoblotting. In vivo, mice were intraperitoneally injected into Dox to establish a heart failure model. Then, different groups of mice were administered either PBS, adeno-associated virus (AAV)-vector, AAV-miR-200b-inhibitor or TSC-Exos via tail vein injection. Then, the cardiac function, cardiac fibrosis and cardiomyocyte apoptosis in each group were evaluated, and the downstream molecular mechanism was explored. TSC-Exos and miR-200b inhibitor both decreased primary cardiomyocyte apoptosis. Similarly, mice receiving TSC-Exos and AAV-miR-200b inhibitor exhibited improved cardiac function, accompanied by reduced apoptosis and inflammation. The bioinformatic prediction and luciferase reporter results confirmed that Zeb1 was a downstream target of miR-200b and had an antiapoptotic effect. TSC-Exos attenuated doxorubicin-induced cardiac injury by playing antiapoptotic and anti-inflammatory roles. The underlying mechanism could be an increase in Zeb1 expression by the inhibition of miR-200b expression. In summary, this study sheds new light on the application of TSC-Exos as a potential therapeutic tool for heart failure.

scholarly journals Human Cytomegalovirus Infection Upregulates the Mitochondrial Transcription and Translation Machineries

mBio ◽  
2016 ◽  
Vol 7 (2) ◽  
Author(s):  
S. Karniely ◽  
M. P. Weekes ◽  
R. Antrobus ◽  
J. Rorbach ◽  
L. van Haute ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Human Cytomegalovirus ◽  
Mitochondrial Biogenesis ◽  
Ribosome Biogenesis ◽  
Hcmv Infection ◽  
Aerobic Glycolysis ◽  
Tricarboxylic Acid Cycle ◽  
Mitochondrial Translation ◽  
Mitochondrial Transcription ◽  
Mitochondrial Ribosome

ABSTRACT Infection with human cytomegalovirus (HCMV) profoundly affects cellular metabolism. Like in tumor cells, HCMV infection increases glycolysis, and glucose carbon is shifted from the mitochondrial tricarboxylic acid cycle to the biosynthesis of fatty acids. However, unlike in many tumor cells, where aerobic glycolysis is accompanied by suppression of mitochondrial oxidative phosphorylation, HCMV induces mitochondrial biogenesis and respiration. Here, we affinity purified mitochondria and used quantitative mass spectrometry to determine how the mitochondrial proteome changes upon HCMV infection. We found that the mitochondrial transcription and translation systems are induced early during the viral replication cycle. Specifically, proteins involved in biogenesis of the mitochondrial ribosome were highly upregulated by HCMV infection. Inhibition of mitochondrial translation with chloramphenicol or knockdown of HCMV-induced ribosome biogenesis factor MRM3 abolished the HCMV-mediated increase in mitochondrially encoded proteins and significantly impaired viral growth under bioenergetically restricting conditions. Our findings demonstrate how HCMV manipulates mitochondrial biogenesis to support its replication. IMPORTANCE Human cytomegalovirus (HCMV), a betaherpesvirus, is a leading cause of morbidity and mortality during congenital infection and among immunosuppressed individuals. HCMV infection significantly changes cellular metabolism. Akin to tumor cells, in HCMV-infected cells, glycolysis is increased and glucose carbon is shifted from the tricarboxylic acid cycle to fatty acid biosynthesis. However, unlike in tumor cells, HCMV induces mitochondrial biogenesis even under aerobic glycolysis. Here, we have affinity purified mitochondria and used quantitative mass spectrometry to determine how the mitochondrial proteome changes upon HCMV infection. We find that the mitochondrial transcription and translation systems are induced early during the viral replication cycle. Specifically, proteins involved in biogenesis of the mitochondrial ribosome were highly upregulated by HCMV infection. Inhibition of mitochondrial translation with chloramphenicol or knockdown of HCMV-induced ribosome biogenesis factor MRM3 abolished the HCMV-mediated increase in mitochondrially encoded proteins and significantly impaired viral growth. Our findings demonstrate how HCMV manipulates mitochondrial biogenesis to support its replication.

THE ROLE OF CARDIOMYOCYTE APOPTOSIS IN THE DEVELOPMENT OF CARDIAC FIBROSIS.

2007 ◽  
Vol 55 (1) ◽  
pp. S84
Author(s):  
T. U. Dyamenahalli ◽  
A. R. Plawman ◽  
J. A. Meznarich ◽  
A. C. Stempien-Otero
Keyword(s):  
Cardiac Fibrosis ◽  
Cardiomyocyte Apoptosis

scholarly journals miR-153-3p Targets βII Spectrin to Regulate Formaldehyde-Induced Cardiomyocyte Apoptosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Panyu Yang ◽  
Yanyan Yang ◽  
Xiangqin He ◽  
Pin Sun ◽  
Ying Zhang ◽  
...  
Keyword(s):  
Rat Model ◽  
Heart Development ◽  
Cardiac Fibrosis ◽  
Apoptotic Cell ◽  
Cardiomyocyte Apoptosis ◽  
Real Time Quantitative Pcr ◽  
Luciferase Activity Assay ◽  
Caspase 7 ◽  
Embryonic Cardiomyocytes ◽  
Mirna Pathway

Background: Formaldehyde (FA) is ubiquitous in the environment and can be transferred to the fetus through placental circulation, causing miscarriage and congenital heart disease (CHD). Studies have shown that βII spectrin is necessary for cardiomyocyte survival and differentiation, and its loss leads to heart development defects and cardiomyocyte apoptosis. Additionally, previous studies have demonstrated that miRNA is essential in heart development and remodeling. However, whether miRNA regulates FA-induced CHD and cardiomyocyte apoptosis remains unclear.Methods: Using commercially available rat embryonic cardiomyocytes and a rat model of fetal cardiomyocyte apoptosis. Real-time quantitative PCR (RT-qPCR) and Western blot were performed to examine the level of miR-153-3p, βII spectrin, caspase 7, cleaved caspase7, Bax, Bcl-2 expression in embryonic cardiomyocytes and a rat model of fetal cardiomyocyte apoptosis. Apoptotic cell populations were evaluated by flow cytometry and Tunel. Luciferase activity assay and RNA pull-down assay were used to detect the interaction between miR-153-3p and βII spectrin. Masson's trichrome staining detects the degree of tissue fibrosis. Fluorescence in situ hybridization (FISH) and Immunohistochemistry were used to detect the expression of miR-153-3p and βII spectrin in tissues.Results: Using commercially available rat embryonic cardiomyocytes and a rat model of fetal cardiomyocyte apoptosis, our studies indicate that miR-153-3p plays a regulatory role by directly targeting βII spectrin to promote cardiomyocyte apoptosis. miR-153-3p mainly regulates cardiomyocyte apoptosis by regulating the expression of caspase7, further elucidating the importance of apoptosis in heart development. Finally, the results with our animal model revealed that targeting the miR-153-3p/βII spectrin pathway effectively regulated FA-induced damage during heart development. Recovery experiments with miR-153-3p antagomir resulted in the reversal of FA-induced cardiomyocyte apoptosis and fetal cardiac fibrosis.Conclusion: This study investigated the molecular mechanism underpinning the role of βII spectrin in FA-induced CHD and the associated upstream miRNA pathway. The study findings suggest that miR-153-3p may provide a potential target for the clinical diagnosis and treatment of CHD.

scholarly journals Ketone Body Metabolism in the Ischemic Heart

2021 ◽  
Vol 8 ◽  
Author(s):  
Stephen C. Kolwicz
Keyword(s):  
Ketone Body ◽  
Ketone Bodies ◽  
Ischemia Reperfusion ◽  
Ischemic Heart ◽  
Myocardial Infarctions ◽  
Ketogenic Diets ◽  
Health And Disease ◽  
Ketone Body Metabolism ◽  
Artery Disease ◽  
Fuel Source

Ketone bodies have been identified as an important, alternative fuel source in heart failure. In addition, the use of ketone bodies as a fuel source has been suggested to be a potential ergogenic aid for endurance exercise performance. These findings have certainly renewed interest in the use of ketogenic diets and exogenous supplementation in an effort to improve overall health and disease. However, given the prevalence of ischemic heart disease and myocardial infarctions, these strategies may not be ideal for individuals with coronary artery disease. Although research studies have clearly defined changes in fatty acid and glucose metabolism during ischemia and reperfusion, the role of ketone body metabolism in the ischemic and reperfused myocardium is less clear. This review will provide an overview of ketone body metabolism, including the induction of ketosis via physiological or nutritional strategies. In addition, the contribution of ketone body metabolism in healthy and diseased states, with a particular emphasis on ischemia-reperfusion (I-R) injury will be discussed.

P282 Elevated serum uric acid associated with both electrocardiographic and echocardiographic left ventricular hypertrophy independent of blood pressure in healthy individuals

2020 ◽  
Vol 41 (Supplement_1) ◽  
Author(s):  
C W Liu ◽  
W C Chang ◽  
R H Pan
Keyword(s):  
Blood Pressure ◽  
Uric Acid ◽  
Left Ventricular Hypertrophy ◽  
Serum Uric Acid ◽  
Ventricular Hypertrophy ◽  
Cardiac Fibrosis ◽  
Elevated Serum ◽  
Left Ventricular ◽  
Healthy Individuals ◽  
Lv Mass

Abstract Funding Acknowledgements TSGH 108-11 Background Elevated serum uric acid (SUA) is associated with cardiac fibrosis and hypertrophy. A growing body of evidence showed the positive correlation between hyperuricemia (HUA) and left ventricular hypertrophy (LVH), but most studies defined LVH by a single method such as electrocardiogram or echocardiogram; the former is generally used in massive screen but the latter take advantage of the accuracy of LVH. Purpose We conducted this study to concomitantly investigate the association between SUA and electrocardiographic and echocardiographic LVH. Methods We initially enrolled 17,913 healthy individuals, who routinely underwent an annual health exam at our hospital between 2016/1/1∼2016/12/31. Of them, 347 individuals received transthoracic echocardiography because of abnormal results in their electrocardiogram. Amplitudes of 12-lead electrocardiogram were artificially measured by a study assistant under the supervision and by artificial intelligence. HUA is defined as an SUA level of ≥7 mg/dl in men and ≥6 mg/dl in women. Electrocardiographic LVH is defined by the criteria of Cornel voltage and product and Sokolow-Lyon and the Minnesota Code ECG classification. Echocardiographic LVH is defined by LV mass index ≥115g/m² in men or ≥95g/m² in women. Results The HUA group (n = 233) vs. normouricemic group (n = 114) was older and predominant male with greater values of body mass index, systolic and diastolic blood pressure and laboratory biomarkers, including non-high density total cholesterol, fasting glucose impairment, creatinine clearance, and haemoglobin. The two groups had comparable lifestyle choices, including tobacco use, alcohol intake, and physical activities per week. The HUA group compared with the normouricemic group had greater values of S amplitude of V1 plus R amplitude of V5 (3031 ± 2055 uV vs. 2566 ± 1021 uV, P = 0.005), R amplitude in lead I plus S amplitude in lead III (842 ± 443 uV vs. 696 ± 386 uV, P = 0.002) and LV mass index (95 ± 23 g/m² vs. 85 ± 30 g/m², P = 0.001). The prevalence of electrocardiographic and echocardiographic LVH was greater in the HUA group than the normouricemic group (7.0% vs. 2.1%, P = 0.034 for electrocardiographic LVH and 15.8% vs. 7.7%, P = 0.025 for echocardiographic LVH). In multivariate logistic regression analyses, elevated SUA was associated with LVH after the confounders were fully adjusted (OR: 1.38, 95% CI: 1.07-1.77, P = 0.012 for electrocardiographic LVH and OR: 1.58, 95% CI 1.15-2.17, P = 0.004 for echocardiographic LVH). Conclusion Elevated SUA is independently associated with the prevalence of both electrocardiographic and echocardiographic LVH in healthy individuals from Taiwan. Future studies might evaluate urate-lowering effects on the regression of LVH.

Polystyrene microplastics cause cardiac fibrosis by activating Wnt/β-catenin signaling pathway and promoting cardiomyocyte apoptosis in rats

2020 ◽  
Vol 265 ◽  
pp. 115025 ◽  
Author(s):  
Zekang Li ◽  
Shuxiang Zhu ◽  
Qian Liu ◽  
Jialiu Wei ◽  
Yinchuan Jin ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cardiac Fibrosis ◽  
Cardiomyocyte Apoptosis

Cardiac PANK1 Deletion Exacerbates Ventricular Dysfunction During Pressure Overload

2021 ◽  
Author(s):  
Timothy N. Audam ◽  
Caitlin M. Howard ◽  
Lauren F. Garrett ◽  
Yi Wei Zheng ◽  
James A. Bradley ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Biosynthetic Pathway ◽  
Ketone Body ◽  
Cardiac Fibrosis ◽  
Ventricular Dysfunction ◽  
Pressure Overload ◽  
Ventricular Dilation ◽  
The Impact ◽  
Rate Limiting

Coenzyme A (CoA) is an essential co-factor required for intermediary metabolism. Perturbations in homeostasis of CoA have been implicated in various pathologies; however, whether CoA homeostasis is changed and the extent to which CoA levels contribute to ventricular function and remodeling during pressure overload has not been explored. In this study, we sought to assess changes in CoA biosynthetic pathway during pressure overload and determine the impact of limiting CoA on cardiac function. We limited cardiac CoA levels by deleting the rate limiting enzyme in CoA biosynthesis, Pank1. We found that constitutive, cardiomyocyte-specific Pank1 deletion (cmPank1-/-) significantly reduced PANK1 mRNA, PANK1 protein, and CoA levels compared to Pank1 sufficient littermates (cmPank1+/+) but exerted no obvious deleterious impact on the mice at baseline. We then subjected both groups of mice to pressure overload-induced heart failure. Interestingly, there was more ventricular dilation in cmPank1-/- during pressure overload. To explore potential mechanisms contributing to this phenotype, we performed transcriptomic profiling, which suggested a role for Pank1 in regulating fibrotic and metabolic processes during pressure overload. Indeed, Pank1 deletion exacerbated cardiac fibrosis following pressure overload. Because we were interested in the possibility of early metabolic impacts in response to pressure overload, we performed untargeted metabolomics, which indicated significant changes to metabolites involved in fatty acid and ketone metabolism, among other pathways. Collectively, our study underscores the role of elevated CoA levels in supporting fatty acid and ketone body oxidation, which may be more important than CoA-driven, enzyme-independent acetylation in the failing heart.

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