Ticagrelor reverses the mitochondrial dysfunction through preventing accumulated autophagosomes-dependent apoptosis and ER stress in insulin-resistant H9c2 myocytes

Homocysteine- (Hcy-) induced endothelial cell apoptosis has been suggested as a cause of Hcy-dependent vascular injury, while the proposed molecular pathways underlying this process are unclear. In this study, we investigated the adverse effects of Hcy on human umbilical vein endothelial cells (HUVEC) and the underlying mechanisms. Our results demonstrated that moderate-dose Hcy treatment induced HUVEC apoptosis in a time-dependent manner. Furthermore, prolonged Hcy treatment increased the expression of NOX4 and the production of intracellular ROS but decreased the ratio of Bcl-2/Bax and mitochondrial membrane potential (MMP), resulting in the leakage of cytochrome c and activation of caspase-3. Prolonged Hcy treatment also upregulated glucose-regulated protein 78 (GRP78), activated protein kinase RNA-like ER kinase (PERK), and induced the expression of C/EBP homologous protein (CHOP) and the phosphorylation of NF-κb. The inhibition of NOX4 decreased the production of ROS and alleviated the Hcy-induced HUVEC apoptosis and ER stress. Blocking the PERK pathway partly alleviated Hcy-induced HUVEC apoptosis and the activation of NF-κb. Taken together, our results suggest that Hcy-induced mitochondrial dysfunction crucially modulated apoptosis and contributed to the activation of ER stress in HUVEC. The excessive activation of the PERK pathway partly contributed to Hcy-induced HUVEC apoptosis and the phosphorylation of NF-κb.

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Hyperbaric oxygen therapy attenuates D-galactose-induced-age-related cardiac dysfunction through mitigating cardiac mitochondrial dysfunction in pre-diabetic rats

European Heart Journal ◽

10.1093/ehjci/ehaa946.3229 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

C Bo-Htay ◽

T Shwe ◽

S Palee ◽

T Pattarasakulchai ◽

K Shinlapawittayatorn ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

High Fat Diet ◽

Diabetic Rats ◽

Normal Diet ◽

Lv Function ◽

High Fat ◽

Insulin Resistant ◽

Lv Dysfunction ◽

Age Related ◽

Mitochondrial Functions

Abstract Background D-galactose (D-gal) induced ageing has been shown to exacerbate left ventricular (LV) dysfunction via worsening of apoptosis and mitochondrial dysfunction in the heart of obese rats. Hyperbaric oxygen therapy (HBOT) has been demonstrated to exert anti-inflammatory and anti-apoptotic effects in multiple neurological disorders. However, the cardioprotective effect of HBOT on inflammation, apoptosis, LV and mitochondrial functions in D-gal induced ageing rats in the presence of obese-insulin resistant condition has never been investigated. Purpose We sought to determine the effect of HBOT on inflammation, apoptosis, mitochondrial functions and LV function in pre-diabetic rats with D-gal induced ageing. We hypothesized that HBOT attenuates D-gal induced cardiac mitochondrial dysfunctions and reduces inflammation and apoptosis, leading to improved LV function in pre-diabetic rats. Methods Forty-eight male Wistar rats were fed with either normal diet or high-fat diet for 12 weeks. Then, rats were treated with either vehicle groups (0.9% NSS, subcutaneous injection (SC)) or D-gal groups (150 mg/kg/day, SC) for 8 weeks. At week 21, rats in each group were equally divided into 6 sub-groups: normal diet fed rats treated with vehicle (NDV) sham, normal diet fed rats treated with D-gal (NDDg) sham, high fat diet fed rats treated with D-gal (HFDg) sham, high fat diet fed rats treated with vehicle (HFV) + HBOT, NDDg + HBOT and HFDg + HBOT. Sham treated rats were given normal concentration of O2 (flow rate of 80 L/min, 1 ATA for 60 minutes), whereas HBOT treated rats were subjected to 100% O2 (flow rate of 250 L/min, 2 ATA for 60 minutes), given once daily for 2 weeks. Results Under obese-insulin resistant condition, D-gal-induced ageing aggravated LV dysfunction (Fig 1A) and impaired cardiac mitochondrial function, increased cardiac inflammatory and apoptotic markers (Fig 1B). HBOT markedly reduced cardiac TNF-α level and TUNEL positive apoptotic cells, and improved cardiac mitochondrial function as indicated by decreased mitochondrial ROS production, mitochondrial depolarization and mitochondrial swelling, resulting in the restoration of the normal LV function in HFV and NDDg rats, compared to sham NDDg rats. In addition, in HFDg treated rats, HBOT attenuated cardiac TNF-α level, TUNEL positive apoptotic cells and cardiac mitochondrial dysfunction, compared to sham HFDg rats, leading to improved cardiac function as indicated by increased %LV ejection fraction (LVEF) (Figure 1). Conclusion HBOT efficiently alleviates D-gal-induced-age-related LV dysfunction through mitigating inflammation, apoptosis and mitochondrial dysfunction in pre-diabetic rats. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): 1. The National Science and Technology Development Agency Thailand, 2. Thailand Research Fund Grants

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ApoE4 (Δ272–299) induces mitochondrial‐associated membrane formation and mitochondrial impairment by enhancing GRP75-modulated mitochondrial calcium overload in neuron

Cell & Bioscience ◽

10.1186/s13578-021-00563-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Tao Liang ◽

Weijian Hang ◽

Jiehui Chen ◽

Yue Wu ◽

Bin Wen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Er Stress ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Calcium Transport ◽

Calcium Overload ◽

Mitochondrial Calcium ◽

Mitochondrial Impairment

Abstract Background Apolipoprotein E4 (apoE4) is a major genetic risk factor of Alzheimer’s disease. Its C-terminal-truncated apoE4 (Δ272–299) has neurotoxicity by affecting mitochondrial respiratory function. However, the molecular mechanism(s) underlying the action of apoE4 (Δ272–299) in mitochondrial function remain poorly understood. Methods The impact of neuronal apoE4 (Δ272–299) expression on ER stress, mitochondrial-associated membrane (MAM) formation, GRP75, calcium transport and mitochondrial impairment was determined in vivo and in vitro. Furthermore, the importance of ER stress or GRP75 activity in the apoE4 (Δ272–299)-promoted mitochondrial dysfunction in neuron was investigated. Results Neuronal apoE4 (Δ272–299) expression induced mitochondrial impairment by inducing ER stress and mitochondrial-associated membrane (MAM) formation in vivo and in vitro. Furthermore, apoE4 (Δ272–299) expression promoted GRP75 expression, mitochondrial dysfunction and calcium transport into the mitochondria in neuron, which were significantly mitigated by treatment with PBA (an inhibitor of ER stress), MKT077 (a specific GRP75 inhibitor) or GRP75 silencing. Conclusions ApoE4 (Δ272–299) significantly impaired neuron mitochondrial function by triggering ER stress, up-regulating GRP75 expression to increase MAM formation, and mitochondrial calcium overload. Our findings may provide new insights into the neurotoxicity of apoE4 (Δ272–299) against mitochondrial function and uncover new therapeutic targets for the intervention of Alzheimer’s disease.

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Chronic treatment with prebiotics, probiotics and synbiotics attenuated cardiac dysfunction by improving cardiac mitochondrial dysfunction in male obese insulin-resistant rats

European Journal of Nutrition ◽

10.1007/s00394-017-1482-3 ◽

2017 ◽

Vol 57 (6) ◽

pp. 2091-2104 ◽

Cited By ~ 30

Author(s):

Wannipa Tunapong ◽

Nattayaporn Apaijai ◽

Sakawdaurn Yasom ◽

Pongpan Tanajak ◽

Keerati Wanchai ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Cardiac Dysfunction ◽

Chronic Treatment ◽

Insulin Resistant

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HIGH-FAT HIGH-CARBOHYDRATE DIET ACCELERATES LEFT-VENTRICULAR DYSFUNCTION FASTER THAN HIGH-FAT DIET ALONE VIA INCREASING MITOCHONDRIAL DYSFUNCTION IN OBESE-INSULIN RESISTANT RATS

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(19)31431-7 ◽

2019 ◽

Vol 73 (9) ◽

pp. 824

Author(s):

Nattayaporn Apaijai ◽

Apiwan Arinno ◽

Siripong Palee ◽

Wasana Pratchayasakul ◽

Sasiwan Kerdphoo ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Left Ventricular Dysfunction ◽

High Fat Diet ◽

Ventricular Dysfunction ◽

Left Ventricular ◽

High Carbohydrate Diet ◽

High Fat ◽

Carbohydrate Diet ◽

Insulin Resistant ◽

High Carbohydrate

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2-Chlorohexadecanoic acid induces ER stress and mitochondrial dysfunction in brain microvascular endothelial cells

Redox Biology ◽

10.1016/j.redox.2018.01.003 ◽

2018 ◽

Vol 15 ◽

pp. 441-451 ◽

Cited By ~ 15

Author(s):

Eva Bernhart ◽

Nora Kogelnik ◽

Jürgen Prasch ◽

Benjamin Gottschalk ◽

Madeleine Goeritzer ◽

...

Keyword(s):

Endothelial Cells ◽

Er Stress ◽

Mitochondrial Dysfunction ◽

Microvascular Endothelial Cells ◽

Brain Microvascular Endothelial Cells ◽

Microvascular Endothelial

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Abstract 16607: Age-induced Endoplasmic Reticulum Stress in the Heart: Role of Increased Very Long-chain Ceramides

Circulation ◽

10.1161/circ.142.suppl_3.16607 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Qun Chen ◽

Anna Kovilakath ◽

Jeremy Allegood ◽

Lauren A Cowart ◽

Edward J Lesnefsky

Keyword(s):

Er Stress ◽

Mitochondrial Dysfunction ◽

Acyl Chain ◽

Membrane Domains ◽

Ceramide Synthase ◽

Age Related ◽

Chain Lengths ◽

Endoplasm Reticulum ◽

Long Chain

Introduction: Mitochondrial function is impaired in aged hearts. Increased endoplasm reticulum (ER) stress contributes to the mitochondrial dysfunction observed during aging. Ceramides (CRMD) are sphingolipid metabolites that contribute key roles in cell signaling. Increased CRMD can lead to ER stress. Ceramide synthase enzymes (CerS) generate chain length specific CRMD with the CerS isoform 2 (Cers2) forming very long chain CRMD of ≥ 20 carbon acyl chain lengths. Hypothesis: An increase in CRMD content during aging contributes to age-related ER stress. Methods: Male mice (3, 18, 24 mo.) from the NIA colony were studied. Cardiac mitochondria (MITO), mitochondrial associated membranes (MAM), and ER were isolated from mouse hearts. CRMD content was measured using LC-MS. The contents of CerS enzymes were measured by immunoblotting in myocardial homogenates. Results: ER stress increased progressively during aging with increased contents of cleaved ATF6 and CHOP, indicators of increased ER stress, evident at 18 and 24 mo. (Panel A) (all data mean±SEM; *p<0.05 vs. 3 mo., † p<0.05 vs. 18 mo.). Aging increased very long-chain CRMD (≥C20) in ER (Panel B) at 18 and 24 mo. Similar CRMD trends were observed MAM (Panel C), shared membrane domains where ER and MITO interact. The content of CerS2 was increased at 24 mo. compared to 3 mo. (Panel D, n=4 each age). In contrast, the contents of CerS isoforms 4 and 5, that generate shorter chain CRMD (<C20) were unchanged (not shown). CRMD contents in MITO were unaltered with age (not shown). Thus, increased generation of very long chain CRMD in the ER is the likely mechanism of increased ER stress in the aged heart. Conclusion: Aging increased ER CRMD content by enhancing the formation of very long chain CRMD in ER by an increase in CerS2 content, concomitant with the onset of ER stress. The increase in age-induced ER stress, in turn, leads to mitochondrial dysfunction in the aged heart.

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Trichomonas Vaginalis Induces Apoptosis via ROS and ER Stress Through ER-mitochondria Crosstalk in Human Cervical Epithelial Cells

10.21203/rs.3.rs-330817/v1 ◽

2021 ◽

Author(s):

Fei Fei Gao ◽

Juan-Hua Quan ◽

Min A Lee ◽

Wei Ye ◽

Jae-Min Yuk ◽

...

Keyword(s):

Stress Response ◽

Epithelial Cells ◽

Er Stress ◽

Mitochondrial Dysfunction ◽

Parasite Burden ◽

Dependent Manner ◽

Ros Production ◽

Er Stress Response ◽

Siha Cells ◽

Mitochondrial Ros

Abstract Background: Human trichomoniasis is one of the most common sexually transmitted infections; however, its pathogenesis remains unclear. Here, we investigated the role of the endoplasmic reticulum (ER) in apoptosis induction by T. vaginalis in human cervical epithelial SiHa cellsMethods: We evaluated the cytotoxicity, apoptosis, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), ER stress response, and Bcl-2 family protein expressions using LDH assay, immunocytochemistry, flow cytometry, JC-1 dye staining, and western blotting.Results: T. vaginalis induced LDH-dependent cytotoxicity, mitochondrial ROS production, and apoptosis in SiHa cells, parasite burden- and infection time-dependently. T. vaginalis also induced ER stress response and mitochondrial dysfunction, such as MMP depolarization and imbalance in levels of Bcl-2 family proteins, in SiHa cells in a parasite burden- and infection time-dependent manner. Pretreatment with N-Acetyl cysteine (ROS scavenger) or 4-phenylbutyric acid (4-PBA, ER stress inhibitor) significantly alleviated apoptosis, ROS production, mitochondrial dysfunction, and ER stress response in a dose-dependent manner. These data suggested that SiHa cell apoptosis is affected by ROS and ER stress after T. gondii infection. In addition, T. vaginalis induced ASK1 and JNK phosphorylation in SiHa cells, however 4-PBA or SP600125 (JNK inhibitor) pretreatment significantly attenuated ASK1/JNK phosphorylation, mitochondrial dysfunction, apoptosis, and ER stress response in SiHa cells, dose-dependently.Conclusions: T. vaginalis induces mitochondrial apoptosis via ROS and parasite-mediated ER stress via the IRE1/ASK1/JNK/Mcl-1 pathways, and also induces ER stress response directly and mitochondrial ROS-dependently in human cervical epithelial SiHa cells, thus, T. vaginalis induces apoptosis via ROS and ER stress through ER-mitochondria crosstalk in human cervical epithelial cells. These results expand our understanding of the molecular mechanisms underlying the pathogenesis of human trichomoniasis.

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Abstract 131: Restoration of ER Stress and Induction of FGF15/19 Independently Rescue ABCG5 ABCG8 Sterol Transporter

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.131 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Yuhuan Wang ◽

Kai Su ◽

Nadezhda Sabeva ◽

Ailing Ji ◽

Deneys van der Westhuyzen ◽

...

Keyword(s):

Bile Acid ◽

Er Stress ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Biliary Cholesterol ◽

Leptin Receptors ◽

Insulin Resistant ◽

Protein Levels ◽

The Face ◽

Biliary Cholesterol Secretion

Mice lacking leptin (ob/ob) or its receptor (db/db) are obese, insulin resistant and have reduced levels of biliary cholesterol due, in part, to reduced levels of hepatic ABCG5 ABCG8 (G5G8). Chronic leptin replacement restores G5G8 abundance and increases biliary cholesterol concentrations, but the molecular mechanism responsible for G5G8 regulation remains unclear. In the current study, we conducted a series of experiments to address potential mechanisms. To determine if leptin signaling directly regulates hepatic G5G8 abundance, we acutely replaced leptin in ob/ob mice and deleted hepatic leptin receptors in lean mice. Neither manipulation altered G5G8 abundance or biliary cholesterol. Similarly, hepatic vagotomy had no effect on G5G8. Alternatively, the G5G8 protein complex may be decreased due to compromised ER stress. It has been previously reported that tauroursodeoxycholate (TUDCA) alleviates ER stress. It also increases G5G8 and biliary cholesterol in both lean and db/db mice. The ER chaperone protein, glucose regulated protein 78-kDa (GRP78) can restore ER function and reduce unfolded protein response (UPR) signaling. Therefore, we tested the hypothesis that expression of GRP78 could rescue G5G8 in db/db mice. Adenovirus encoding GRP78 was administered to db/db mice and the effect on hepatic G5G8 was determined. G5 and G8 proteins and biliary cholesterol were increased in the absence of changes in mRNAs encoding either protein. However, TUDCA has also been shown to induce FGF15. In several models of bile acid feeding, FGF15/19 is stimulated in ileum and activates its receptor in liver to repress bile acid synthesis. Simultaneously, G5G8 and biliary cholesterol secretion are elevated. To determine if FGF15/19 had a direct effect on hepatic G5G8, we injected C57BL/6 mice with recombinant FGF19. CYP7A1 and CYP8B1 mRNA expression were both strongly suppressed, whereas G5G8 increased at both mRNA and protein levels. In conclusion, G5G8 can be rescued in ob/ob and db/db mice through multiple mechanisms that include restoration of ER functions and FGF15/19 signaling. Counter regulation of CYP7A1, CYP8B1, and G5G8 by FGF15/19 allows for the maintenance of hepatic sterol elimination in the face of expanded bile acid pool.

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