Sarco/endoplasmic Reticulum Calcium ATPase-2 Expression Is Regulated by ATF6 during the Endoplasmic Reticulum Stress Response

Thuerauf, Donna J.; Hoover, Holly; Meller, Julia; Hernandez, Jessica; Su, Leo Y.; Andrews, Catherine A.; Dillmann, Wolfgang H.; McDonough, Patrick M.; Glembotski, Christopher C.

doi:10.1074/jbc.m107146200

Cited by 84 publications

(73 citation statements)

References 46 publications

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“…XBP-1s is translocated to the nucleus where it binds to ER stress-response elements (ERSE) and/or unfolded protein response elements (UPRE) in the promoters of target genes (Lee et al, 2003). In line with this study, SERCA2b whose promoters contain three ERSE (Thuerauf et al, 2001) was upregulated in dTHP-1 macrophages. The Ca 2+ -ATPase activity of SERCA2b enzyme can be affected by the physico-chemical properties of the membrane in which these enzymes are embedded (Starling et al 1996;Li et al 2004).…”

Section: Disruption Of Er Homeostasis Triggers Uprsupporting

confidence: 66%

PPAR&#947 Ligand-Induced Unfolded Protein Responses in Monocytes and Macrophages

Isa¹,

Morris²,

Thomas³

et al. 2011

Nig J Bas App Sci

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168ABSTRACT: Obesity and associated disorders such as Type-2 Diabetes (T2D) and atherosclerosis are associated with elevated levels of circulating oxidized low-density lipoprotein (oxLDL). High levels of oxLDL lead to cell dysfunction and apoptosis, a phenomenon known as lipotoxicity. Disturbing endoplasmic reticulum (ER) function results in ER stress and unfolded protein response (UPR), which tends to restore ER homeostasis but switches to apoptosis when ER stress is prolonged. In the present study the lipotoxic effect of oxLDL was investigated on a monocyte/macrophage cell lines. The results demonstrate that oxLDL could induce ER stress and activation of the UPR pathway in mnocyte/macrophage cell lines as evident of the activation/up-regulation of ER stress/UPR genes. Cholesterol does not seem to exert effects in intact cells in our experiments; in contrast oxLDL did induce ER stress and UPR. In microsomal fractions, cholesterol but not oxLDL inhibit the ER Ca 2+ -ATPase activity. Gene expression analysis showed that macrophages express high levels of the oxLDL scavenger receptor CD36, than monocytes and oxLDL induced macrophage apoptosis via caspase-3/7 activation. The observations that oxLDL can induce UPRs in macrophages, and that cholesterol inhibit ER Ca 2+ -ATPase activity, suggest that cholesterol may be the oxLDL component responsible for macrophage lipotoxic ER stress effects as seen in obesity. As disrupted cellular Ca 2+ homeostasis/ER stress may be linked to macrophage lipotoxicity this data may enhance our understanding of the diverse effects of oxLDL, particularly in the context of obesity, type 2 diabetes and metabolic syndrome.

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Section: Disruption Of Er Homeostasis Triggers Uprsupporting

confidence: 66%

PPAR&#947 Ligand-Induced Unfolded Protein Responses in Monocytes and Macrophages

Isa¹,

Morris²,

Thomas³

et al. 2011

Nig J Bas App Sci

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“…It has been reported that the expression and activity of SERCA2b, the other spliced protein of the SERCA2 gene, could be induced by the UPR pathway in the PC12 cell line during ER stress (26,27). In the cardiomyocytes, SERCA2a expression could be upregulated as a potential physiologically important compensatory mechanism by ATF6 in response to sarcoplasmic reticulum calcium depletion-induced ER stress (28). In our study, although the ATF6 branch of UPR was activated, we did not find an increased SERCA2a protein level in the IHD+EGFP group.…”

Section: Discussioncontrasting

confidence: 46%

“…Early observations showed that alteration of sarcoplasmic reticulum/ER Ca 2+ levels below functional acceptable limits enhances the ER stress, and SERCA2 expression and activity could be induced during ER stress in cardiomyocytes and other cells, suggesting a potential role of SERCA2a protein in ER stress (26)(27)(28). Because the major function of SERCA2a is to replenish the sarcoplasmic reticulum Ca 2+ load during the contraction-relaxation cycle of the heart (29), which is fundamental to the ER function of protein folding, we hypothesized that restoration of SERCA2a expression by recombinant adeno-associated virus 1 (rAAV1)-mediated gene delivery could maintain the ER function and attenuate ER stress-associated myocardial apoptosis in an IHD pig model.…”

Section: Attenuation Of Endoplasmic Reticulum Stress-related Myocardimentioning

confidence: 99%

Attenuation of Endoplasmic Reticulum Stress-Related Myocardial Apoptosis by SERCA2a Gene Delivery in Ischemic Heart Disease

Wei

et al. 2010

Mol Med

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Previous studies suggested that endoplasmic reticulum (ER) stress-associated apoptosis plays an important role in the pathogenesis of ischemic heart disease. Gene transfer of sarco/endoplasmic reticulum Ca 2+ ATPase 2a (SERCA2a) attenuates myocardial apoptosis in a variety of heart failure models. This study is to investigate the effects of SERCA2a gene delivery on the myocardial apoptosis and ER stress pathway in a porcine ischemic heart disease model. Eighteen pigs were either subjected to ameroid implantation in the coronary artery or sham operation. Eight wks after gene delivery, the protein level and activity of SERCA2a were measured. Myocardial apoptosis was determined using terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling assay. Regional myocardial perfusion and function were evaluated by 99m Tc-sestamibi ( 99m Tc-MIBI) single photon emission computed tomography and echocardiography. The ER stress signaling was assessed by Western blot. SERCA2a protein level and activity were significantly decreased in the ischemic myocardium and restored to normal after SERCA2a gene transfer. Restoration of SERCA2a expression significantly improved the cardiac function, although no improvement of regional myocardial perfusion was detected. Restoration of SERCA2a significantly attenuated myocardial apoptosis and reversed the activation of unfolded protein response (UPR) pathway and the ER stress-associated apoptosis pathways. These findings demonstrate a robust role of SERCA2a in attenuation of ischemic myocardial apoptosis, correlating with reverse activation of the ER stress-associated apoptosis pathways, suggesting that the beneficial effects of SERCA2a gene transfer may involve the attenuation of ER stress-associated myocardial apoptosis.

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“…5). Regulation of the SERCA2 gene is enormously complex with a number of transcription factors/ promoter elements having been implicated (26,(55)(56)(57). Our preliminary studies, based on gene transfer of activated mutants of NF-ATc4 and ␤-catenin, suggest that these known GSK-3␤ targets are not sufficient by themselves to induce SERCA2a gene expression (data not shown), and thus, the GSK-3␤ target regulating SERCA2a expression remains to be identified.…”

Section: Discussionmentioning

confidence: 95%

Glycogen Synthase Kinase-3β Regulates Growth, Calcium Homeostasis, and Diastolic Function in the Heart

Michael

Haq

Chen

et al. 2004

Journal of Biological Chemistry

124

106

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Glycogen synthase kinase (GSK) 3␤ is a negative regulator of stress-induced cardiomyocyte hypertrophy. It is not clear, however, if GSK-3␤ plays any role in regulating normal cardiac growth and cardiac function. Herein we report that a transgenic mouse expressing wild type GSK-3␤ in the heart has a dramatic impairment of normal post-natal cardiomyocyte growth as well as markedly abnormal cardiac contractile function. The most striking phenotype, however, is grossly impaired diastolic relaxation, which leads to increased filling pressures of the left ventricle and massive atrial enlargement. This is due to profoundly abnormal calcium handling, leading to an inability to normalize cytosolic [Ca 2؉ ] in diastole. The alterations in calcium handling are due at least in part to direct down-regulation of the sarcoplasmic reticulum calcium ATPase (SERCA2a) by GSK-3␤, acting at the level of the SERCA2 promoter. These studies identify GSK-3␤ as a regulator of normal growth of the heart and are the first of which we are aware, to demonstrate regulation of expression of SERCA2a, a critical determinant of diastolic function, by a cytosolic signaling pathway, the activity of which is dynamically modulated. De-regulation of GSK-3␤ leads to severe systolic and diastolic dysfunction and progressive heart failure. Because down-regulation of SERCA2a plays a central role in the diastolic and systolic dysfunction of patients with heart failure, these findings have potential implications for the therapy of this disorder.

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Sarco/endoplasmic Reticulum Calcium ATPase-2 Expression Is Regulated by ATF6 during the Endoplasmic Reticulum Stress Response

Cited by 84 publications

References 46 publications

PPAR&#947 Ligand-Induced Unfolded Protein Responses in Monocytes and Macrophages

PPAR&#947 Ligand-Induced Unfolded Protein Responses in Monocytes and Macrophages

Attenuation of Endoplasmic Reticulum Stress-Related Myocardial Apoptosis by SERCA2a Gene Delivery in Ischemic Heart Disease

Glycogen Synthase Kinase-3β Regulates Growth, Calcium Homeostasis, and Diastolic Function in the Heart

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