Reduction of AMP-Activated Protein Kinase α2 Increases Endoplasmic Reticulum Stress and Atherosclerosis In Vivo

Dong, Yunzhou; Zhang, Miao; Liang, Bin; Xie, Zhonglin; Zhao, Zhengxing; Asfa, Sima; Choi, Hyoung Chul; Zou, Ming

doi:10.1161/circulationaha.109.900928

Cited by 242 publications

(223 citation statements)

References 51 publications

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“…Interestingly, it has been reported that reduction in AMPK levels promotes ER stress, suggesting that AMPK functions as a physiological suppressor of ER stress [20]. When we examined the potential mechanisms responsible for the increase in ER stress following palmitate exposure and the protective effects of oleate, we observed that the saturated fatty acid reduced phospho-AMPK levels.…”

Section: Discussionmentioning

confidence: 82%

“…Oleate prevents palmitate-induced ER stress through an AMPK-dependent mechanism It is worth noting that activation of AMPK, which is considered a pharmacological target for insulin resistance and type 2 diabetes mellitus [35], inhibits ER stress [18,19,21] whereas reduction of this kinase promotes ER stress [20]. To confirm a role for AMPK in the preventive effects of oleate on palmitateinduced ER stress in C2C12 myotubes, we used the AMPK activators AICAR and A-769662 and the AMPK inhibitor compound C. The increase in the expression of sXbp1, Atf3, Chop and Bip caused by palmitate was reduced in cells coincubated with palmitate plus either AICAR or A-769662 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Of note, activation of AMPactivated protein kinase (AMPK) exhibits multiple protective effects, including inhibition of inflammation, oxidative stress and insulin resistance and reduces the risk for developing obesity and type 2 diabetes [17]. Recently it has been reported that AMPK activation protects against hypoxic injury [18], atherosclerosis [19,20] and lipid-induced hepatic disorders [21] by reducing ER stress.…”

Section: Introductionmentioning

confidence: 99%

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Oleate prevents saturated-fatty-acid-induced ER stress, inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism

et al. 2013

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Aims/hypothesis Although the substitution of saturated fatty acids with oleate has been recommended in the management of type 2 diabetes mellitus, the mechanisms by which oleate improves insulin resistance in skeletal muscle cells are not completely known. Here, we examined whether oleate, through activation of AMP-activated protein kinase (AMPK), prevented palmitate-induced endoplasmic reticulum (ER) stress, which is involved in the link between lipid-induced inflammation and insulin resistance. Methods Studies were conducted in mouse C2C12 myotubes and in the human myogenic cell line LHCN-M2. To analyse the involvement of AMPK, activators and inhibitors of this kinase and overexpression of a dominant negative AMPK construct (K45R) were used. Results Palmitate increased the levels of ER stress markers, whereas oleate did not. In palmitate-exposed cells incubated with a lower concentration of oleate, the effects of palmitate were prevented. The induction of ER stress markers by palmitate was prevented by the presence of the AMPK activators AICAR and A-769662. Moreover, the ability of oleate to prevent palmitate-induced ER stress and inflammation (nuclear factor-kappa B [NF-κB] DNA-binding activity and expression and secretion of IL6) as well as insulinstimulated Akt phosphorylation and 2-deoxyglucose uptake was reversed in the presence of the AMPK inhibitor compound C or by overexpression of a dominant negative AMPK construct. Finally, palmitate reduced phospho-AMPK levels, whereas this was not observed in oleateexposed cells or in palmitate-exposed cells supplemented with oleate. Conclusions/interpretation Overall, these findings indicate that oleate prevents ER stress, inflammation and insulin resistance in palmitate-exposed skeletal muscle cells by activating AMPK.

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Section: Discussionmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Oleate prevents saturated-fatty-acid-induced ER stress, inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism

et al. 2013

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“…Increased levels of GRP78 were observed in atherosclerotic regions from C57BL6 mice [91] . Dong et al [91] reported that in human umbilical vein endothelial cells and aortic endothelial cells from 5' adenosine monophosphate-activated protein kinase 2 (AMPK2)-deficient C57BL6 mice, the level of ERS increased. Reduction of AMPK2 expression significantly increased ERS levels in human umbilical vein endothelial cells.…”

Section: Endoplasmic Reticulum Stress Regulates Cardiovascular Physiomentioning

confidence: 90%

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

2016

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Endoplasmic reticulum is a principal organelle responsible for folding, post-translational modifications and transport of secretory, luminal and membrane proteins, thus palys an important rale in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) is a condition that is accelerated by accumulation of unfolded/misfolded proteins after endoplasmic reticulum environment disturbance, triggered by a variety of physiological and pathological factors, such as nutrient deprivation, altered glycosylation, calcium depletion, oxidative stress, DNA damage and energy disturbance, etc. ERS may initiate the unfolded protein response (UPR) to restore cellular homeostasis or lead to apoptosis. Numerous studies have clarified the link between ERS and cardiovascular diseases. This review focuses on ERS-associated molecular mechanisms that participate in physiological and pathophysiological processes of heart and blood vessels. In addition, a number of drugs that regulate ERS was introduced, which may be used to treat cardiovascular diseases. This review may open new avenues for studying the pathogenesis of cardiovascular diseases and discovering novel drugs targeting ERS.

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“…Similarly the endothelial cell, just like the pancreatic -cell, when exposed to hyperglycaemia responds with an increase in ER stress that seems to be secondary to mitochondria metabolism and superoxide generation (SheikhAli et al, 2010a). Of additional interest and relevant to the protective role of resveratrol is that ER stress in endothelial cell is enhanced with the deletion of AMPK2 and that certain antioxidants can reduce ER stress (Dong et al, 2010;Sheikh-Ali et al, 2010b).…”

Section: Endoplasmic Reticulum (Er) Stress and Diabetesmentioning

confidence: 99%

Glycaemic Control and Protection of the Vasculature from Glucose Toxicity

Ding¹,

Triggle²

2011

Medical Complications of Type 2 Diabetes

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Reduction of AMP-Activated Protein Kinase α2 Increases Endoplasmic Reticulum Stress and Atherosclerosis In Vivo

Cited by 242 publications

References 51 publications

Oleate prevents saturated-fatty-acid-induced ER stress, inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism

Oleate prevents saturated-fatty-acid-induced ER stress, inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

Glycaemic Control and Protection of the Vasculature from Glucose Toxicity

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