Distinct cardiac energy metabolism and oxidative stress adaptations between obese and non-obese type 2 diabetes mellitus

Li, Xinghui; Wu, Yandi; Zhao, Jingjing; Wang, Haiping; Tan, Jing; Yang, Ming; Li, Yuanlong; Deng, Shijie; Gao, Saifei; Li, Hui; Yang, Zhenyu; Yang, Fengmin; Ma, Jian-Xing; Cheng, Jianding; Cai, Weibin

doi:10.7150/thno.40735

Cited by 40 publications

(36 citation statements)

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“…Ectopically deposited fatty acids in the heart result in lipotoxicity, injury to cardiomyocytes, and myocardial apoptosis (3). PAL, also known as hexadecane, is a commonly consumed saturated fatty acid.…”

Section: Discussionmentioning

confidence: 99%

“…Palmitate (PAL), a saturated fatty acid, has been shown to accumulate in cardiomyocytes, vascular smooth muscle cells, hepatic cells, and islet beta cells (8)(9)(10)(11)(12). PAL accumulation in cardiomyocytes can lead to "lipotoxicity" and thus result in cardiomyocyte injury, apoptosis, and heart dysfunction and failure (3,(13)(14)(15). Transgenic mouse models with abnormal lipid accumulation in the heart demonstrated that an imbalance of lipid uptake and utilization in cardiomyocytes led to apoptosis and contributed to cardiomyopathy (16,17).…”

Section: Introductionmentioning

confidence: 99%

“…However, the latest research shows that cardiomyocyte apoptosis is also an important biological basis for the normal physiological function of the heart (1). The rapid changes in the human diet, and the concomitant increase in human fat deposition, have led to a high incidence of obesity, diabetes, and cardiovascular diseases (3). Increases in serum lipid levels result in damage to and irritation of the cardiovascular system; particularly, ectopic fat deposition places an additional burden on the heart, which can lead to myocardial injury (4).…”

Section: Introductionmentioning

confidence: 99%

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Vascular Endothelial Growth Factor Ameliorated Palmitate Induced Cardiomyocyte Injury via JNK Pathway

Wang

Zou

Liu³

et al. 2020

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Objective To investigate the effect of palmitate (PAL) on apoptosis and the timing and activity of VEGF expression in HHHM2 myocardial cells (a human embryonic cardiomyocyte cell- line). Methods 1. Cardiomyocytes were divided into the following five groups: the control group and the 0.2 mM, 0.5 mM, 0.8 mM, and 1.2 mM PAL groups. We examined the changes in cell viability by MTT assay after PAL incubation for 24 h and the cardiomyocyte apoptosis rate by FACS examination, and thus determined the effective concentration of PAL. The transcription levels of CASP3, Bcl-2, Bax, and VEGF were detected by quantitative fluorescence PCR and the protein expression of caspase 3 and VEGF by western blot. 2. To observe the time-dependent effects on cell injury induced by 0.5 mM PAL, cardiomyocytes were divided into 0, 4, 8, 16, 24, and 48 h groups. The variation in cell viability was examined by MTT assay. The transcription levels of CASP3, Bcl-2, Bax, and VEGF were detected by quantitative fluorescence PCR and the protein expression of caspase 3 and VEGF by western blot. 3. To observe the effects of VEGF on the PAL induced apoptosis of cardiomyocytes, the cells were divided into the control group and the VEGF overexpression group. At 24 h after transfection, cells were incubated with 0.5 mM PAL for 6, 12, 24, and 48 h. Cell viability was examined by MTT assay. The apoptosis rate was measured by FACS using the Annexin V-FITC kit. The transcription levels of CASP3, Bcl-2, Bax, NF-kB p65, and VEGF were measured by quantitative fluorescence PCR, the protein expression of VEGF, caspase 3, Bcl-2, Bax, NF-κB p65, p-JNK/JNK, and p-ERK/ERK were measured by western blot, as well as caspase 3 activity. Results 1. A dose-dependent relation between the concentration of PAL and H9c2 cardiomyocyte injury was observed. In the 0.5 mM group, the apoptosis rate was increased significantly, while cell viability was decreased, indicating that 0.5 mM PAL was the ideal concentration to induce cardiomyocyte apoptosis. The expression of caspase 3 and Bax was significantly increased, and the expression of VEGF was enhanced, while the levels of Bcl-2 remained unchanged during the process. 2. A significant time-dependent relation between PAL and cardiomyocyte injury was observed. The apoptosis rate was increased greatly after 16 h treatment with 0.5 mM PAL. 3. Cell viability was restored by VEGF overexpression during treatment with 0.5 mM PAL. The apoptosis rate was also reduced by VEGF overexpression, as detected by FACS. The expression of caspase 3, Bax, and NF-κB p65 was significantly decreased, Bcl-2 and VEGF expression was dramatically increased, p-JNK/JNK expression was significantly enhanced, p-ERK/ERK levels did not exhibit a significant change, and the activity of caspase 3 was significantly decreased. Conclusions 1. PAL can induce injury and apoptosis in HHHM2 myocardial cells, and these effects are time-dependent. A PAL concentration of 0.5 mM was ideal to establish the cardiac cell injury model. 2. PAL at a concentration of 0.5 mM can effectively induce cardiomyocyte injury and enhance the expression of caspase 3, Bax, and VEGF, especially after 24 h and 48 h of PAL treatment. 3. VEGF overexpression can reverse the effects of PAL on apoptosis and cell viability. In addition, VEGF overexpression inhibited the expression of proapoptotic and inflammatory factors, caspase 3 activity, and transduction of the MAPK signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Vascular Endothelial Growth Factor Ameliorated Palmitate Induced Cardiomyocyte Injury via JNK Pathway

Wang

Zou

Liu³

et al. 2020

Preprint

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“…In children and teenagers, severe obesity was reported to increase the risk of T2DM compared with that in adults 9 . Persistent myocardial lipid toxicity in obese type 2 diabetics was more likely to cause cardiac systolic dysfunction than in non-obese patients 10 . In addition, obese people were 3.5 times more likely to develop high blood pressure 11 .…”

Section: Introductionmentioning

confidence: 94%

PPARα mediates night neon light-induced weight gain: role of lipid homeostasis

et al. 2020

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Rationale: Light pollution leads to high risk of obesity but the underlying mechanism is not known except for the influence of altered circadian rhythm. Peroxisome proliferator-activated receptor α (PPARα) regulates lipid metabolism, but its role in circadian-related obesity is not clear. Methods: Wild-type (WT) and Ppara- null (KO) mice on a high-fat diet (HFD) were treated with neon light at night for 6 weeks. Body weights were recorded and diet consumption measured. The hypothalamus, liver, adipose and serum were collected for mechanism experimentation. Results: WT mice on a HFD and exposed to night neon light gained about 19% body weight more than the WT control mice without light exposure and KO control mice on a HFD and exposed to night neon light. The increase in adipose tissue weight and adipocyte size led to the differences in body weights. Biochemical analysis suggested increased hepatic lipid accumulated and increased transport of lipid from the liver to peripheral tissues in the WT mice that gained weight under neon light exposure. Unlike KO mice, the expression of genes involved in lipid metabolism and the circadian factor circadian locomotor output cycles kaput (CLOCK) in both liver and adipose tissues were elevated in WT mice under neon light exposure. Conclusions: PPARα mediated weight gain of HFD-treated mice exposed to night neon light. More lipids were synthesized in the liver and transported to peripheral tissue leading to adaptive metabolism and lipid deposition in the adipose tissue. These data revealed an important mechanism of obesity induced by artificial light pollution where PPARα was implicated.

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“…Nrf2 is a cap'n'collar (CNC) basic-region leucine zipper (bZIP) nuclear transcription factor. Current evidence has demonstrated that GSK-3β manipulates nuclear exclusion and degradation of Nrf2 via the regulation of β-Trcp, which acts as a scaffolding protein for the Skp1-Cull-Rbx1/Roc1 ubiquitin ligase complex 63 , 64 .…”

Section: Downstream Effectors Of Gsk-3βmentioning

confidence: 99%

Glycogen synthase kinase-3β: a promising candidate in the fight against fibrosis

et al. 2020

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Fibrosis exists in almost all organs/tissues of the human body, plays an important role in the occurrence and development of diseases and is also a hallmark of the aging process. However, there is no effective prevention or therapeutic method for fibrogenesis. As a serine/threonine (Ser/Thr)-protein kinase, glycogen synthase kinase-3β (GSK-3β) is a vital signaling mediator that participates in a variety of biological events and can inhibit extracellular matrix (ECM) accumulation and the epithelial-mesenchymal transition (EMT) process, thereby exerting its protective role against the fibrosis of various organs/tissues, including the heart, lung, liver, and kidney. Moreover, we further present the upstream regulators and downstream effectors of the GSK-3β pathway during fibrosis and comprehensively summarize the roles of GSK-3β in the regulation of fibrosis and provide several potential targets for research. Collectively, the information reviewed here highlights recent advances vital for experimental research and clinical development, illuminating the possibility of GSK-3β as a novel therapeutic target for the management of tissue fibrosis in the future.

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Distinct cardiac energy metabolism and oxidative stress adaptations between obese and non-obese type 2 diabetes mellitus

Cited by 40 publications

References 1 publication

Vascular Endothelial Growth Factor Ameliorated Palmitate Induced Cardiomyocyte Injury via JNK Pathway

Vascular Endothelial Growth Factor Ameliorated Palmitate Induced Cardiomyocyte Injury via JNK Pathway

PPARα mediates night neon light-induced weight gain: role of lipid homeostasis

Glycogen synthase kinase-3β: a promising candidate in the fight against fibrosis

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