scholarly journals Ketogenic Diet Suppressed T-Regulatory Cells and Promoted Cardiac Fibrosis via Reducing Mitochondria-Associated Membranes and Inhibiting Mitochondrial Function

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Jun Tao ◽  
Hao Chen ◽  
Ya-Jing Wang ◽  
Jun-Xiong Qiu ◽  
Qing-Qi Meng ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Cardiac Function ◽  
Ketogenic Diet ◽  
Mitochondrial Respiration ◽  
Cardiac Fibrosis ◽  
Interstitial Fibrosis ◽  
Diabetic Patients ◽  
T Regulatory Cell ◽  
Metabolic Indices ◽  
And Function

Ketogenic diet (KD) is popular in diabetic patients but its cardiac safety and efficiency on the heart are unknown. The aim of the present study is to determine the effects and the underlined mechanisms of KD on cardiac function in diabetic cardiomyopathy (DCM). We used db/db mice to model DCM, and different diets (regular or KD) were used. Cardiac function and interstitial fibrosis were determined. T-regulatory cell (Treg) number and functions were evaluated. The effects of ketone body (KB) on fatty acid (FA) and glucose metabolism, mitochondria-associated endoplasmic reticulum membranes (MAMs), and mitochondrial respiration were assessed. The mechanisms via which KB regulated MAMs and Tregs were addressed. KD improved metabolic indices in db/db mice. However, KD impaired cardiac diastolic function and exacerbated ventricular fibrosis. Proportions of circulatory CD4+CD25+Foxp3+ cells in whole blood cells and serum levels of IL-4 and IL-10 were reduced in mice fed with KD. KB suppressed the differentiation to Tregs from naive CD4+ T cells. Cultured medium from KB-treated Tregs synergically activated cardiac fibroblasts. Meanwhile, KB inhibited Treg proliferation and productions of IL-4 and IL-10. Treg MAMs, mitochondrial respiration and respiratory complexes, and FA synthesis and oxidation were all suppressed by KB while glycolytic levels were increased. L-carnitine reversed Treg proliferation and function inhibited by KB. Proportions of ST2L+ cells in Tregs were reduced by KB, as well as the production of ST2L ligand, IL-33. Reinforcement expressions of ST2L in Tregs counteracted the reductions in MAMs, mitochondrial respiration, and Treg proliferations and productions of Treg cytokines IL-4 and IL-10. Therefore, despite the improvement of metabolic indices, KD impaired Treg expansion and function and promoted cardiac fibroblast activation and interstitial fibrosis. This could be mainly mediated by the suppression of MAMs and fatty acid metabolism inhibition via blunting IL-33/ST2L signaling.

Kir6.1 improves cardiac dysfunction in diabetic cardiomyopathy via the AKT-Foxo1 signaling pathway

2020 ◽  
Author(s):  
Jinxin Wang ◽  
Jing Bai ◽  
Peng Duan ◽  
Hao Wang ◽  
Yang Li ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Signaling Pathway ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Diabetic Patients ◽  
Protein Levels ◽  
Inwardly Rectifying Potassium Channel ◽  
Transmission Electron ◽  
Hematoxylin And Eosin ◽  
And Function

Abstract Background: Diabetic cardiomyopathy (DCM) severely impairs the health of diabetic patients. Previous studies have shown that the expression of inwardly rectifying potassium channel 6.1 (Kir6.1) in heart mitochondria is significantly reduced in type 1 diabetes. However, whether its expression and function are changed and what role it plays in type 2 DCM have not been reported. This study investigated the role and mechanism of Kir6.1 in DCM.Methods: The cardiac function in mice was analyzed by echocardiography, ELISA, hematoxylin and eosin staining, TUNEL and transmission electron microscopy. The mitochondrial function in cardiomyocytes was measured by the oxygen consumption rate and the mitochondrial membrane potential (ΔΨm). Kir6.1 expression at the mRNA and protein levels was analyzed by quantitative real-time PCR and western blotting (WB), respectively. The protein expression of t-AKT, p-AKT, t-Foxo1, and p-Foxo1 was analyzed by WB.Results: We found that the cardiac function and the Kir6.1 expression in DCM mice were decreased. Kir6.1 overexpression improved cardiac dysfunction and upregulated the phosphorylation of AKT and Foxo1 in the DCM mouse model. Furthermore, Kir6.1 overexpression also improved cardiomyocyte dysfunction and upregulated the phosphorylation of AKT and Foxo1 in cardiomyocytes with insulin resistance. In contrast, cardiac-specific Kir6.1 knockout aggravated the cardiac dysfunction and downregulated the phosphorylation of AKT and Foxo1 in DCM mice. Furthermore, Foxo1 activation downregulated the expression of Kir6.1 and decreased the ΔΨm in cardiomyocytes. In contrast, Foxo1 inactivation upregulated the expression of Kir6.1 and increased the ΔΨm in cardiomyocytes. Chromatin immunoprecipitation assay demonstrated that the Kir6.1 promoter region contains a functional Foxo1-binding site .Conclusions: Kir6.1 improves cardiac dysfunction in DCM, probably through the AKT-Foxo1 signaling pathway. Moreover, the crosstalk between Kir6.1 and the AKT-Foxo1 signaling pathway may provide new strategies for reversing the defective signaling in DCM.

scholarly journals Melatonin Ameliorates MI-Induced Cardiac Remodeling and Apoptosis through a JNK/p53-Dependent Mechanism in Diabetes Mellitus

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Linhe Lu ◽  
Jipeng Ma ◽  
Mingming Sun ◽  
Xiaowu Wang ◽  
Erhe Gao ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Interstitial Fibrosis ◽  
Myocardial Dysfunction ◽  
Cardiac Injury ◽  
Diabetic Patients ◽  
High Fat ◽  
Adult Mice ◽  
Cardiac Geometry ◽  
And Function

Diabetes mellitus, a worldwide health threat, is considered an independent risk factor for cardiovascular diseases. The overall cardiovascular risk of diabetes is similar to the one having one myocardial infarction (MI) attack although the precise impact of diabetes on MI-induced myocardial anomalies remains elusive. Given that mortality following MI is much greater in diabetic patients compared to nondiabetic patients, this study was designed to examine the effect of melatonin on MI injury-induced myocardial dysfunction in diabetes. Adult mice were made diabetic using high-fat feeding and streptozotocin (100 mg/kg body weight) prior to MI and were treated with melatonin (50 mg/kg/d, p.o.) for 4 weeks prior to assessment of cardiac geometry and function. The MI procedure in diabetes displayed overt changes in cardiac geometry (chamber dilation and interstitial fibrosis) and functional anomalies (reduced fractional shortening and cardiomyocyte contractile capacity) in association with elevated c-Jun N-terminal kinase (JNK) phosphorylation and p53 level. Melatonin treatment markedly attenuated cardiac dysfunction and myocardial fibrosis in post-MI diabetic mice. Furthermore, melatonin decreased JNK phosphorylation, reduced p53 levels, and suppressed apoptosis in hearts from the post-MI diabetic group. In vitro findings revealed that melatonin effectively counteracted high-glucose/high fat-hypoxia-induced cardiomyocyte apoptosis and contractile dysfunction through a JNK-mediated mechanism, the effects of which were impaired by the JNK activator anisomycin. In summary, our study suggests that melatonin protects against myocardial injury in post-MI mice with diabetes, which offers a new therapeutic strategy for the management of MI-induced cardiac injury in diabetes.

The coiled-coil domain of MURC/cavin-4 is involved in membrane trafficking of caveolin-3 in cardiomyocytes

2015 ◽  
Vol 309 (12) ◽  
pp. H2127-H2136 ◽  
Author(s):  
Daisuke Naito ◽  
Takehiro Ogata ◽  
Tetsuro Hamaoka ◽  
Naohiko Nakanishi ◽  
Kotaro Miyagawa ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cardiac Function ◽  
Membrane Trafficking ◽  
Protein Level ◽  
Interstitial Fibrosis ◽  
Coiled Coil ◽  
Cardiomyocyte Hypertrophy ◽  
Coiled Coil Domain ◽  
Cytoplasmic Proteins ◽  
And Function

Muscle-restricted coiled-coil protein (MURC), also referred to as cavin-4, is a member of the cavin family that works cooperatively with caveolins in caveola formation and function. Cavins are cytoplasmic proteins with coiled-coil domains and form heteromeric complexes, which are recruited to caveolae in cells expressing caveolins. Among caveolins, caveolin-3 (Cav3) is exclusively expressed in muscle cells, similar to MURC/cavin-4. In the heart, Cav3 overexpression contributes to cardiac protection, and its deficiency leads to progressive cardiomyopathy. Mutations in the MURC/cavin-4 gene have been identified in patients with dilated cardiomyopathy. In the present study, we show the role of MURC/cavin-4 as a caveolar component in the heart. In H9c2 cells, MURC/cavin-4 was localized at the plasma membrane, whereas a MURC/cavin-4 mutant lacking the coiled-coil domain (ΔCC) was primarily localized to the cytoplasm. ΔCC bound to Cav3 and impaired membrane localization of Cav3 in cardiomyocytes. Additionally, although ΔCC did not alter Cav3 mRNA expression, ΔCC decreased the Cav3 protein level. MURC/cavin-4 and ΔCC similarly induced cardiomyocyte hypertrophy; however, ΔCC showed higher hypertrophy-related fetal gene expression than MURC/cavin-4. ΔCC induced ERK activation in cardiomyocytes. Transgenic mice expressing ΔCC in the heart (ΔCC-Tg mice) showed impaired cardiac function accompanied by cardiomyocyte hypertrophy and marked interstitial fibrosis. Hearts from ΔCC-Tg mice showed a reduction of the Cav3 protein level and activation of ERK. These results suggest that MURC/cavin-4 requires its coiled-coil domain to target the plasma membrane and to stabilize Cav3 at the plasma membrane of cardiomyocytes and that MURC/cavin-4 functions as a crucial caveolar component to regulate cardiac function.

Comparison of isoproterenol and dobutamine in the induction of cardiac hypertrophy and fibrosis

Perfusion ◽  
2008 ◽  
Vol 23 (4) ◽  
pp. 231-235 ◽  
Author(s):  
M Anderson ◽  
D Moore ◽  
DF Larson
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Cardiac Fibrosis ◽  
Detrimental Effect ◽  
Chronic Administration ◽  
Atrial Size ◽  
Term Administration ◽  
And Function ◽  
Induce Heart Failure

Isoproterenol (Iso) was a clinical therapeutic that is now used as a research means for the induction of cardiac hypertrophy. Currently, dobutamine (Dob) has replaced Iso as the preferred inotropic β-adrenergic agent to wean patients from cardiopulmonary bypass and to sustain adequate cardiac function during the postoperative period. We sought to compare the cardiac structural and functional effects of long-term administration (7days) of Iso with Dob at a dose of 40μg/mouse/day in 12-week-old C57BL/6 female mice. Cardiac function was determined with transthoracic echo cardiography (ECHO) 24 hours after the last dose. Cardiac wet weights increased 33% and 24% in the Iso and Dob groups compared with controls ( p < 0.05). Dob and Iso significantly increased cardiac fibrosis and decreased cardiac function with chronic administration. Administration also resulted in increased left atrial size, suggesting that both Dob and Iso decreased LV compliance, but did not induce heart failure. In conclusion, chronic administration of Dob may have a detrimental effect on cardiac structure and function.

scholarly journals Gut-Derived Metabolite Indole-3-Propionic Acid Modulates Mitochondrial Function in Cardiomyocytes and Alters Cardiac Function

2021 ◽  
Vol 8 ◽  
Author(s):  
Maren Gesper ◽  
Alena B. H. Nonnast ◽  
Nina Kumowski ◽  
Robert Stoehr ◽  
Katharina Schuett ◽  
...  
Keyword(s):  
Heart Failure ◽  
Endothelial Cells ◽  
Fatty Acid ◽  
Cardiac Function ◽  
Mitochondrial Dysfunction ◽  
Propionic Acid ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Acid Oxidation ◽  
Microbial Metabolites

Background: The gut microbiome has been linked to the onset of cardiometabolic diseases, in part facilitated through gut microbiota-dependent metabolites such as trimethylamine-N-oxide. However, molecular pathways associated to heart failure mediated by microbial metabolites remain largely elusive. Mitochondria play a pivotal role in cellular energy metabolism and mitochondrial dysfunction has been associated to heart failure pathogenesis. Aim of the current study was to evaluate the impact of gut-derived metabolites on mitochondrial function in cardiomyocytes via an in vitro screening approach.Methods: Based on a systematic Medline research, 25 microbial metabolites were identified and screened for their metabolic impact with a focus on mitochondrial respiration in HL-1 cardiomyocytes. Oxygen consumption rate in response to different modulators of the respiratory chain were measured by a live-cell metabolic assay platform. For one of the identified metabolites, indole-3-propionic acid, studies on specific mitochondrial complexes, cytochrome c, fatty acid oxidation, mitochondrial membrane potential, and reactive oxygen species production were performed. Mitochondrial function in response to this metabolite was further tested in human hepatic and endothelial cells. Additionally, the effect of indole-3-propionic acid on cardiac function was studied in isolated perfused hearts of C57BL/6J mice.Results: Among the metabolites examined, microbial tryptophan derivative indole-3-propionic acid could be identified as a modulator of mitochondrial function in cardiomyocytes. While acute treatment induced enhancement of maximal mitochondrial respiration (+21.5 ± 7.8%, p &lt; 0.05), chronic exposure led to mitochondrial dysfunction (−18.9 ± 9.1%; p &lt; 0.001) in cardiomyocytes. The latter effect of indole-3-propionic acids could also be observed in human hepatic and endothelial cells. In isolated perfused mouse hearts, indole-3-propionic acid was dose-dependently able to improve cardiac contractility from +26.8 ± 11.6% (p &lt; 0.05) at 1 μM up to +93.6 ± 14.4% (p &lt; 0.001) at 100 μM. Our mechanistic studies on indole-3-propionic acids suggest potential involvement of fatty acid oxidation in HL-1 cardiomyocytes.Conclusion: Our data indicate a direct impact of microbial metabolites on cardiac physiology. Gut-derived metabolite indole-3-propionic acid was identified as mitochondrial modulator in cardiomyocytes and altered cardiac function in an ex vivo mouse model.

scholarly journals 2-Arachidonoylglycerol Attenuates Fibrosis in Diabetic Mice via the TGF-β1/Smad Pathway

2021 ◽  
Author(s):  
Zhengjie Chen ◽  
Liangyu Zheng ◽  
Gang Chen
Keyword(s):  
Cardiac Function ◽  
Myocardial Fibrosis ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Heart Function ◽  
Myocardial Cell ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Tgf Β1

Abstract Purpose: Diabetic cardiomyopathy (DM) is the cause of late cardiac dysfunction in diabetic patients. Myocardial fibrosis is the main pathological mechanism, which is associated with transforming growth factor-β1(TGF-β1) expression up-regulation. 2-Arachidonoylglycerol (2-AG) is an endogenous cannabinoid that can effectively improve myocardial cell energy metabolism and cardiac function. Here, we evaluated the protective effect of 2-AG on diabetic cardiomyopathy.Methods: Male C57BL/6J mice were injected with 2-AG intraperitoneally for 4 weeks (1μg/kg/day) after 12 weeks of diabetic modeling. After 4 weeks, heart function was evaluated by echocardiography. Heart structure was assessed by hematoxylin and eosin staining. Cardiac fibrosis was analyzed using immunohistochemistry, Sirius red stain and Western blot.Results: After modeling in diabetic mice, cardiac ultrasonography showed decreased cardiac function, and pathological findings showed that myocardial fibrosis. 2-AG could effectively inhibit the up-regulation of TGF-β1 and Smad2/3, improve myocardial fibrosis and ultimately improve cardiac function in diabetic mice.Conclusion: 2-AG reduces cardiac fibrosis via the TGF-β1/Smad2/3 pathway and is a potential pathway for the treatment of cardiac dysfunction in diabetic mice.

scholarly journals The α11 integrin mediates fibroblast–extracellular matrix–cardiomyocyte interactions in health and disease

2016 ◽  
Vol 311 (1) ◽  
pp. H96-H106 ◽  
Author(s):  
Robert A. Civitarese ◽  
Ilana Talior-Volodarsky ◽  
Jean-Francois Desjardins ◽  
Golam Kabir ◽  
Jennifer Switzer ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Connexin 43 ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Diastolic Pressure ◽  
Interstitial Fibrosis ◽  
Mouse Heart ◽  
Wild Type ◽  
The Impact

Excessive cardiac interstitial fibrosis impairs normal cardiac function. We have shown that the α11β1 (α11) integrin mediates fibrotic responses to glycated collagen in rat myocardium by a pathway involving transforming growth factor-β. Little is known of the role of the α11 integrin in the developing mammalian heart. Therefore, we examined the impact of deletion of the α11 integrin in wild-type mice and in mice treated with streptozotocin (STZ) to elucidate the role of the α11 integrin in normal cardiac homeostasis and in the pathogenesis of diabetes-related fibrosis. As anticipated, cardiac fibrosis was reduced in α11 integrin knockout mice (α11−/−; C57BL/6 background) treated with STZ compared with STZ-treated wild-type mice ( P < 0.05). Unexpectedly, diastolic function was impaired in both vehicle and STZ-treated α11−/− mice, as shown by the decreased minimum rate of pressure change and prolonged time constant of relaxation in association with increased end-diastolic pressure (all P < 0.05 compared with wild-type mice). Accordingly, we examined the phenotype of untreated α11−/− mice, which demonstrated a reduced cardiomyocyte cross-sectional cell area and myofibril thickness (all P < 0.05 compared with wild-type mice) and impaired myofibril arrangement. Immunostaining for desmin and connexin 43 showed abnormal intermediate filament organization at intercalated disks and impaired gap-junction development. Overall, deletion of the α11 integrin attenuates cardiac fibrosis in the mammalian mouse heart and reduces ECM formation as a result of diabetes. Furthermore, α11 integrin deletion impairs cardiac function and alters cardiomyocyte morphology. These findings shed further light on the poorly understood interaction between the fibroblast–cardiomyocyte and the ECM.

Unaltered Fatty Acid Uptake, Utilization, and Mitochondrial Respiration in Right Atrial Appendage of Type 2 Diabetic Human Heart

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 335-OR
Author(s):  
NANDINI RJ ◽  
SR RAJI ◽  
VIVEK V. PILLAI ◽  
JAYAKUMAR K. ◽  
SRINIVAS GOPALA
Keyword(s):  
Fatty Acid ◽  
Mitochondrial Respiration ◽  
Human Heart ◽  
Fatty Acid Uptake ◽  
Atrial Appendage ◽  
Right Atrial ◽  
Acid Uptake ◽  
Right Atrial Appendage ◽  
Type 2 Diabetic

scholarly journals A Low-Carbohydrate Ketogenic Diet and Treadmill Training Enhanced Fatty Acid Oxidation Capacity but Did Not Enhance Maximal Exercise Capacity in Mice

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 611
Author(s):  
Sihui Ma ◽  
Jiao Yang ◽  
Takaki Tominaga ◽  
Chunhong Liu ◽  
Katsuhiko Suzuki
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Exercise Capacity ◽  
Ketogenic Diet ◽  
Maximal Exercise ◽  
Treadmill Running ◽  
Acid Oxidation ◽  
Oxidation Capacity ◽  
Low Carbohydrate ◽  
Maximal Exercise Capacity

The low-carbohydrate ketogenic diet (LCKD) is a dietary approach characterized by the intake of high amounts of fat, a balanced amount of protein, and low carbohydrates, which is insufficient for metabolic demands. Previous studies have shown that an LCKD alone may contribute to fatty acid oxidation capacity, along with endurance. In the present study, we combined a 10-week LCKD with an 8-week forced treadmill running program to determine whether training in conjunction with LCKD enhanced fatty acid oxidation capacity, as well as whether the maximal exercise capacity would be affected by an LCKD or training in a mice model. We found that the lipid pool and fatty acid oxidation capacity were both enhanced following the 10-week LCKD. Further, key fatty acid oxidation related genes were upregulated. In contrast, the 8-week training regimen had no effect on fatty acid and ketone body oxidation. Key genes involved in carbohydrate utilization were downregulated in the LCKD groups. However, the improved fatty acid oxidation capacity did not translate into an enhanced maximal exercise capacity. In summary, while favoring the fatty acid oxidation system, an LCKD, alone or combined with training, had no beneficial effects in our intensive exercise-evaluation model. Therefore, an LCKD may be promising to improve endurance in low- to moderate-intensity exercise, and may not be an optimal choice for those partaking in high-intensity exercise.

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