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heat failure and endoplasmic reticulum

Dylan J Dues, Emily K Andrews, Claire E Schaar, Alexis L Bergsma, Megan M Senchuk, Jeremy M Van Raamsdonk
In this work, we examine the relationship between stress resistance and aging. We find that resistance to multiple types of stress peaks during early adulthood and then declines with age. To dissect the underlying mechanisms, we use C. elegans transcriptional reporter strains that measure the activation of different stress responses including: the heat shock response, mitochondrial unfolded protein response, endoplasmic reticulum unfolded protein response, hypoxia response, SKN-1-mediated oxidative stress response, and the DAF-16-mediated stress response...
April 2016: Aging
Y Xie, W Hou, X Song, Y Yu, J Huang, X Sun, R Kang, D Tang
Ferroptosis is a recently recognized form of regulated cell death. It is characterized morphologically by the presence of smaller than normal mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista, and outer mitochondrial membrane rupture. It can be induced by experimental compounds (e.g., erastin, Ras-selective lethal small molecule 3, and buthionine sulfoximine) or clinical drugs (e.g., sulfasalazine, sorafenib, and artesunate) in cancer cells and certain normal cells (e...
March 2016: Cell Death and Differentiation
Stephen R Hennigar, Vanessa Velasquez, Shannon L Kelleher
BACKGROUND: Lactation failure is common in overweight and obese women; however, the precise mechanism remains unknown. OBJECTIVE: We tested the hypothesis that obesity-induced inflammation in the mammary gland (MG) redistributes subcellular zinc pools to promote cell death of mammary epithelial cells (MECs) and premature involution. METHODS: Female DBA/2J mice were fed a high-fat (obese; 45% kcal from fat, n = 60) or control diet (lean; 10% kcal from fat, n = 50) for 5 wk and bred...
September 2015: Journal of Nutrition
James Won Suk Jahng, Subat Turdi, Vera Kovacevic, Keith Dadson, Ren-Ke Li, Gary Sweeney
Heart failure is a leading cause of death, especially in the elderly or obese and diabetic populations. Various remodeling events have been characterized, which collectively contribute to the progression of heart failure. Of particular interest, autophagy has recently emerged as an important determinant of cardiac remodeling and function. Here, we used aged, 13-month-old, male adiponectin knockout (Ad-KO) or wild-type (wt) mice subjected to aortic banding to induce pressure overload (PO). Cardiac strain analysis using speckle tracking echocardiography indicated significant dysfunction at an earlier stage in Ad-KO than wt...
July 2015: Endocrinology
Subhalakshmi Ganguly, Arkadeep Mitra, Sagartirtha Sarkar
Cardiovascular disease is the leading cause of death worldwide. Recently emerging evidence suggests that cardiomyocyte apoptosis is one of the major pathogenic factors in heart diseases leading to heart failure. Cardiomyocytes undergo apoptosis in response to a wide variety of cellular stresses including protein folding stress at Endoplasmic reticulum (ER). Stressed myocytes elicit an adaptive response referred as Unfolded Protein Response (UPR) by inducing accumulation of heat shock proteins (HSPs) to mitigate the ER stress...
2014: Cardiovascular & Hematological Agents in Medicinal Chemistry
Shuang Chen, Liang Zhou, Yu Zhang, Yun Leng, Xin-Yan Pei, Hui Lin, Richard Jones, Robert Z Orlowski, Yun Dai, Steven Grant
In selective autophagy, the adaptor protein SQSTM1/p62 plays a critical role in recognizing/loading cargo (e.g., malfolded proteins) into autophagosomes for lysosomal degradation. Here we report that whereas SQSTM1/p62 levels fluctuated in a time-dependent manner during autophagy, inhibition or knockdown of Cdk9/cyclin T1 transcriptionally downregulated SQSTM1/p62 but did not affect autophagic flux. These interventions, or short hairpin RNA (shRNA) directly targeting SQSTM1/p62, resulted in cargo loading failure and inefficient autophagy, phenomena recently described for Huntington's disease neurons...
September 15, 2014: Molecular and Cellular Biology
Xiaoyu Liu, Dongmin Kwak, Zhongbing Lu, Xin Xu, John Fassett, Huan Wang, Yidong Wei, Douglas R Cavener, Xinli Hu, Jennifer Hall, Robert J Bache, Yingjie Chen
Studies have reported that development of congestive heart failure is associated with increased endoplasmic reticulum stress. Double stranded RNA-activated protein kinase R-like endoplasmic reticulum kinase (PERK) is a major transducer of the endoplasmic reticulum stress response and directly phosphorylates eukaryotic initiation factor 2α, resulting in translational attenuation. However, the physiological effect of PERK on congestive heart failure development is unknown. To study the effect of PERK on ventricular structure and function, we generated inducible cardiac-specific PERK knockout mice...
October 2014: Hypertension
Huan Guo, Yi Xiong, Piotr Witkowski, Jingqing Cui, Ling-jia Wang, Jinhong Sun, Roberto Lara-Lemus, Leena Haataja, Kathryn Hutchison, Shu-ou Shan, Peter Arvan, Ming Liu
Among the defects in the early events of insulin biosynthesis, proinsulin misfolding and endoplasmic reticulum (ER) stress have drawn increasing attention as causes of β cell failure. However, no studies have yet addressed potential defects at the cytosolic entry point of preproinsulin into the secretory pathway. Here, we provide the first evidence that inefficient translocation of preproinsulin (caused by loss of a positive charge in the n region of its signal sequence) contributes to β cell failure and diabetes...
June 6, 2014: Journal of Biological Chemistry
Alberto Bartolomé, Maki Kimura-Koyanagi, Shun-Ichiro Asahara, Carlos Guillén, Hiroyuki Inoue, Kyoko Teruyama, Shinobu Shimizu, Ayumi Kanno, Ana García-Aguilar, Masato Koike, Yasuo Uchiyama, Manuel Benito, Tetsuo Noda, Yoshiaki Kido
Hyperactivation of the mammalian target of rapamycin complex 1 (mTORC1) in β-cells is usually found as a consequence of increased metabolic load. Although it plays an essential role in β-cell compensatory mechanisms, mTORC1 negatively regulates autophagy. Using a mouse model with β-cell-specific deletion of Tsc2 (βTsc2(-/-)) and, consequently, mTORC1 hyperactivation, we focused on the role that chronic mTORC1 hyperactivation might have on β-cell failure. mTORC1 hyperactivation drove an early increase in β-cell mass that later declined, triggering hyperglycemia...
September 2014: Diabetes
Dan Wu, Jing Liu, Baiyan Wu, Bo Tu, Weiguo Zhu, Jianyuan Luo
Mutations in CLN3 gene cause juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease), an early-onset neurodegenerative disorder that is characterized by the accumulation of ceroid lipofuscin within lysosomes. The function of the CLN3 protein remains unclear and is presumed to be related to Endoplasmic reticulum (ER) stress. To investigate the function of CLN3 in the ER stress signaling pathway, we measured proliferation and apoptosis in cells transfected with normal and mutant CLN3 after treatment with the ER stress inducer tunicamycin (TM)...
April 25, 2014: Biochemical and Biophysical Research Communications
N Suganya, E Bhakkiyalakshmi, S Suriyanarayanan, R Paulmurugan, K M Ramkumar
OBJECTIVE: Endothelial dysfunction highlights that it is a potential contributor in the pathogenesis of vascular complications arising from endoplasmic reticulum stress (ER stress) and has been emerging as a main causative factor in vascular failure. Here, we hypothesize that the natural flavonoid, quercetin plays an effective role in reducing ER stress in human umbilical vein endothelial cells. MATERIALS AND METHODS: Human umbilical vein endothelial cells were pre-treated with different concentrations of quercetin (0-100 μm) before inducing ER stress using tunicamycin (TUN) (0...
June 2014: Cell Proliferation
Guido Tarone, Mara Brancaccio
Despite major advances in the treatment of cardiac diseases, there is still a great need for drugs capable of counteracting the deterioration of cardiac muscle function in congestive heart failure. The role of misfolded protein accumulation as a causal event in the physiopathology of common cardiac diseases is an important emerging concept. Indeed, diverse stress conditions, including mechanical stretching and oxidative stress, can induce misfolded protein accumulation, causing cardiomyocyte death. Cells react to these stress conditions by activating molecular chaperones, a class of proteins that represents an endogenous salvage machinery, essential for rescuing physiological cell functions and sustaining cell survival...
June 1, 2014: Cardiovascular Research
Yune-Jung Park, Seung-Ah Yoo, Wan-Uk Kim
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by abnormal proliferation of synoviocytes, leukocyte infiltration, and angiogenesis. The endoplasmic reticulum (ER) is the site of biosynthesis for all secreted and membrane proteins. The accumulation of unfolded proteins in the ER leads to a condition known as ER stress. Failure of the ER's adaptive capacity results in abnormal activation of the unfolded protein response. Recently, we have demonstrated that ER stress-associated gene signatures are highly expressed in RA synovium and synovial cells...
January 2014: Journal of Korean Medical Science
Rodolfo Villarreal-Calderon, Maricela Franco-Lira, Angélica González-Maciel, Rafael Reynoso-Robles, Lou Harritt, Beatriz Pérez-Guillé, Lara Ferreira-Azevedo, Dan Drecktrah, Hongtu Zhu, Qiang Sun, Ricardo Torres-Jardón, Mariana Aragón-Flores, Ana Calderón-Garcidueñas, Philippe Diaz, Lilian Calderón-Garcidueñas
Mexico City Metropolitan Area children and young adults exposed to high concentrations of air pollutants including fine and ultrafine particulate matter (PM) vs. clean air controls, exhibit myocardial inflammation and inflammasome activation with a differential right and left ventricular expression of key inflammatory genes and inflammasomes. We investigated the mRNA expression levels of the prion protein gene PRNP, which plays an important role in the protection against oxidative stress and metal toxicity, and the glucose regulated protein 78, a key protein in endoplasmic reticulum (ER) stress signaling, in ventricular autopsy samples from 30 children and young adults age 19...
November 28, 2013: International Journal of Molecular Sciences
Lewis J Watson, Bethany W Long, Angelica M DeMartino, Kenneth R Brittian, Ryan D Readnower, Robert E Brainard, Timothy D Cummins, Lakshmanan Annamalai, Bradford G Hill, Steven P Jones
The singly coded gene O-linked-β-N-acetylglucosamine (O-GlcNAc) transferase (Ogt) resides on the X chromosome and is necessary for embryonic stem cell viability during embryogenesis. In mature cells, this enzyme catalyzes the posttranslational modification known as O-GlcNAc to various cellular proteins. Several groups, including our own, have shown that acute increases in protein O-GlcNAcylation are cardioprotective both in vitro and in vivo. Yet, little is known about how OGT affects cardiac function because total body knockout (KO) animals are not viable...
January 1, 2014: American Journal of Physiology. Heart and Circulatory Physiology
Rui Zhang, Noreen Rapin, Zhengxin Ying, Erika Shklanka, Timothy W Bodnarchuk, Valerie M K Verge, Vikram Misra
Cells respond to perturbations in the microenvironment of the endoplasmic reticulum (ER), and to the overloading of its capacity to process secretory and membrane-associate proteins, by activating the Unfolded Protein Response (UPR). Genes that mediate the UPR are regulated by three basic leucine-zipper (bLZip) motif-containing transcription factors - Xbp1s, ATF4 and ATF6. A failure of the UPR to achieve homeostasis and its continued stimulation leads to apoptosis. Mechanisms must therefore exist to turn off the UPR if it successfully restores normalcy...
2013: PloS One
Ingo Amm, Thomas Sommer, Dieter H Wolf
Mistakes are part of our world and constantly occurring. Due to transcriptional and translational failures, genomic mutations or diverse stress conditions like oxidation or heat misfolded proteins are permanently produced in every compartment of the cell. As misfolded proteins in general lose their native function and tend to aggregate several cellular mechanisms have been evolved dealing with such potentially toxic protein species. Misfolded proteins are mostly recognized by chaperones on the basis of their exposed hydrophobic patches and, if unable to refold them to their native state, are targeted to proteolytic pathways...
January 2014: Biochimica et Biophysica Acta
A Mitra, T Basak, K Datta, S Naskar, S Sengupta, S Sarkar
Cardiac hypertrophy and myocardial infarction (MI) are two major causes of heart failure with different etiologies. However, the molecular mechanisms associated with these two diseases are not yet fully understood. So, this study was designed to decipher the process of cardiomyocyte apoptosis during cardiac hypertrophy and MI in vivo. Our study revealed that mitochondrial outer membrane channel protein voltage-dependent anion channel-1 (VDAC1) was upregulated exclusively during cardiac hypertrophy, whereas 78 kDa glucose-regulated protein (GRP78) was exclusively upregulated during MI, which is an important upstream regulator of the endoplasmic reticulum (ER) stress pathway...
2013: Cell Death & Disease
Zhi-Qing Fu, Xiao-Ying Li, Xiao-Chun Lu, Ya-Fei Mi, Tao Liu, Wei-Hua Ye
BACKGROUND: Previous studies showed that overexpression of sarco-endoplasmic reticulum calcium ATPase (SERCA2a) in a variety of heart failure (HF) models was associated with greatly enhanced cardiac performance. However, it still undefined the effect of SERCA2a overexpression on the systemic inflammatory response and neuro-hormonal factors. METHODS: A rapid right ventricular pacing model of experimental HF was used in beagles. Then the animals underwent recombinant adeno-associated virus 1 (rAAV1) mediated gene transfection by direct intra-myocardium injection...
September 2012: Journal of Geriatric Cardiology: JGC
Sayuri Takayanagi, Riga Fukuda, Yuuki Takeuchi, Sakiko Tsukada, Kenichi Yoshida
In the endoplasmic reticulum (ER), secretory and membrane proteins are properly folded and modified, and the failure of these processes leads to ER stress. At the same time, unfolded protein response (UPR) genes are activated to maintain homeostasis. Despite the thorough characterization of the individual gene regulation of UPR genes to date, further investigation of the mutual regulation among UPR genes is required to understand the complex mechanism underlying the ER stress response. In this study, we aimed to reveal a gene regulatory network formed by UPR genes, including immunoglobulin heavy chain-binding protein (BiP), X-box binding protein 1 (XBP1), C/EBP [CCAAT/enhancer-binding protein]-homologous protein (CHOP), PKR-like endoplasmic reticulum kinase (PERK), inositol-requiring 1 (IRE1), activating transcription factor 6 (ATF6), and ATF4...
January 2013: Cell Stress & Chaperones
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