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Moritz Horn, Virginia Kroef, Kira Allmeroth, Nicole Schuller, Stephan Miethe, Martin Peifer, Josef M Penninger, Ulrich Elling, Martin S Denzel
Forward genetic screens in haploid mammalian cells have recently emerged as powerful tools for the discovery and investigation of recessive traits. Use of the haploid system provides unique genetic tractability and resolution. Upon positive selection, these screens typically employ analysis of loss-of-function (LOF) alleles and are thus limited to non-essential genes. Many relevant compounds, including anti-cancer therapeutics, however, target essential genes, precluding positive selection of LOF alleles. Here, we asked whether the use of random and saturating chemical mutagenesis might enable screens that identify essential biological targets of toxic compounds...
February 9, 2018: Oncotarget
Chia-Ti Tsai, Ming-Wei Kuo, Jiunn-Lee Lin, Alice L Yu, John Yu
Heart failure is a major cardiovascular disease and is associated with significant morbidity and mortality. Sudden cardiac death (SCD) in heart failure is a disastrous cardiovascular phenomenon. However, few studies have examined the genetic background that determines susceptibility to heart failure and SCD. We found that deficiency of a newly identified gene, Yulink, promoted cardiac alternans in zebrafish cardiomyocytes, and genetic knockdown (KD) resulted in pericardial edema, decreased cardiac output, and premature ventricular contractions...
January 11, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Viviana Meraviglia, Leonardo Bocchi, Roberta Sacchetto, Maria Cristina Florio, Benedetta M Motta, Corrado Corti, Christian X Weichenberger, Monia Savi, Yuri D'Elia, Marcelo D Rosato-Siri, Silvia Suffredini, Chiara Piubelli, Giulio Pompilio, Peter P Pramstaller, Francisco S Domingues, Donatella Stilli, Alessandra Rossini
SERCA2a is the Ca2+ ATPase playing the major contribution in cardiomyocyte (CM) calcium removal. Its activity can be regulated by both modulatory proteins and several post-translational modifications. The aim of the present work was to investigate whether the function of SERCA2 can be modulated by treating CMs with the histone deacetylase (HDAC) inhibitor suberanilohydroxamic acid (SAHA). The incubation with SAHA (2.5 µM, 90 min) of CMs isolated from rat adult hearts resulted in an increase of SERCA2 acetylation level and improved ATPase activity...
January 31, 2018: International Journal of Molecular Sciences
Cameron G McCarthy, Camilla Ferreira Wenceslau, Safia Ogbi, Theodora Szasz, R Clinton Webb
Traditionally, Toll-like receptor (TLR)9 signals through a MyD88-dependent cascade that results in pro-inflammatory gene transcription. Recently it was reported that TLR9 also participates in a stress tolerance signaling cascade in non-immune cells. In this non-canonical pathway, TLR9 binds to and inhibits sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2), modulating intracellular calcium handling, and subsequently resulting in the activation of 5'-AMP-activated protein kinase (AMPK)α. We have previously reported TLR9 causes increased contraction in isolated arteries; however, the mechanisms underlying this vascular dysfunction need to be further clarified...
January 18, 2018: Journal of Pharmacology and Experimental Therapeutics
Liang Zhang, Xiao Yan, Jie Bai, Tesfaldet Habtemariam Hidru, Qing-Shan Wang, Hui-Hua Li
Vitamin D (VD) and its analogues play critical roles in metabolic and cardiovascular diseases. Recent studies have demonstrated that VD exerts a protective role in cardiovascular diseases. However, the beneficial effect of VD on pressure overload-induced cardiac remodeling and dysfunction and its underlying mechanisms are not fully elucidated. In this study, cardiac dysfunction and hypertrophic remodeling in mice were induced by pressure overload. Cardiac function was evaluated by echocardiography, and myocardial histology was detected by H&E and Masson's trichrome staining...
January 11, 2018: Journal of Steroid Biochemistry and Molecular Biology
Tingxin Zhang, Shaopeng Chi, Fan Jiang, Qiancheng Zhao, Bailong Xiao
Piezo proteins are bona fide mammalian mechanotransduction channels for various cell types including endothelial cells. The mouse Piezo1 of 2547 residues forms a three-bladed, propeller-like homo-trimer comprising a central pore-module and three propeller-structures that might serve as mechanotransduction-modules. However, the mechanogating and regulation of Piezo channels remain unclear. Here we identify the sarcoplasmic /endoplasmic-reticulum Ca2+ ATPase (SERCA), including the widely expressed SERCA2, as Piezo interacting proteins...
November 27, 2017: Nature Communications
Min Li, Naoyuki Higashi, Hajime Nakano, Hidehisa Saeki
Darier disease (DD) is a rare autosomal dominant skin disorder due to mutations in the ATP2A2 gene, which encodes sarco/endoplasmic reticulum Ca(2+) ATPase isoform 2 (SERCA2). The clinical manifestations of DD are characterized by warty papules and plaques in seborrheic areas, and association with neuropsychiatric abnormalities has also been reported in a few families with DD. We herein report a classic Japanese DD case with a previously described mutation (p.C560R) in ATP2A2. In Japan, 26 mutations in the ATP2A2 gene in 7 pedigrees and 19 sporadic cases with DD have been reported, among which one pedigree and one sporadic case were accompanied by neuropsychiatric symptoms...
2017: Journal of Nippon Medical School, Nippon Ika Daigaku Zasshi
Sebastian Martewicz, Elena Serena, Susi Zatti, Gordon Keller, Nicola Elvassore
Physical cues are major determinants of cellular phenotype and evoke physiological and pathological responses on cell structure and function. Cellular models aim to recapitulate basic functional features of their in vivo counterparts or tissues in order to be of use in in vitro disease modeling or drug screening and testing. Understanding how culture systems affect in vitro development of human pluripotent stem cell (hPSC)-derivatives allows optimization of cellular human models and gives insight in the processes involved in their structural organization and function...
October 16, 2017: Stem Cell Research
Deng-Cheng Zhou, Yong-Hui Su, Fu-Qing Jiang, Jing-Bo Xia, Hai-Yan Wu, Zao-Shang Chang, Wen-Tao Peng, Guo-Hua Song, Kyu-Sang Park, Soo-Ki Kim, Dong-Qing Cai, Li Zheng, Xu-Feng Qi
Unmethylated CpG oligodeoxynucleotide (CpG-ODN), a Toll-like receptor 9 (TLR9) ligand, has been shown to protect against myocardial ischemia/reperfusion injury. However, the potential effects of CpG-ODN on myocardial infarction (MI) induced by persistent ischemia remains unclear. Here, we investigated whether and how CpG-ODN preconditioning protects against MI in mice. C57BL/6 mice were treated with CpG-ODN by i.p. injection 2 hr prior to MI induction, and cardiac function, and histology were analyzed 2 weeks after MI...
October 23, 2017: Journal of Cellular Physiology
Asvi A Francois, Kofo Obasanjo-Blackshire, James E Clark, Andrii Boguslavskyi, Mark R Holt, Peter Parker, Michael S Marber, Richard J Heads
Aims: PKN1 is a stress-responsive protein kinase acting downstream of small GTP-binding proteins of the Rho/Rac family. The aim was to determine its role in endogenous cardioprotection. Methods and Results: Hearts from PKN1 knockout (KO) or wild type (WT) littermate control mice were perfused in Langendorff mode and subjected to global ischemia and reperfusion (I/R). Myocardial infarct size was doubled in PKN1 KO hearts compared to WT hearts. PKN1 was basally phosphorylated on the activation loop Thr778 PDK1 target site which was unchanged during I/R...
October 16, 2017: Cardiovascular Research
Yusuf Olgar, Murat Cenk Celen, Bilge Eren Yamasan, Nihal Ozturk, Belma Turan, Semir Ozdemir
Recent studies have implicated a relationship between RhoA/ROCK activity and defective Ca(2+) homeostasis in hypertrophic hearts. This study investigated molecular mechanism underlying ROCK inhibition-mediated cardioprotection against pressure overload-induced cardiac hypertrophy, with a focus on Ca(2+) homeostasis. Cardiac hypertrophy model was established by performing transverse aortic constriction (TAC) in 8-week-old male rats. Groups were assigned as SHAM, TAC and TAC+Fas (rats undergoing TAC and treated with fasudil)...
November 2017: Cell Calcium
Somayeh Javidanpour, Mahin Dianat, Mohammad Badavi, Seyyed Ali Mard
Acute myocardial infarction (AMI) is a common cause of hospitalisation and high mortality due to lethal arrhythmias. Sarcoplasmic reticulum Ca2+ ATPase (SERCA2 ) and ryanodine receptor (RyR2 ) regulate the cytosolic Ca2+ ion concentration. Rosmarinic acid (RA) is one of the most common caffeic esters in Rosmarinus officinalis. The present study was conducted to test the hypothesis whether RA can protect cardiac function against AMI and arrhythmias induced by isoproterenol through the regulatory effect of SERCA2 and RyR2 gene expression...
December 2017: Free Radical Research
Rafael Zanelli Rissoli, Eliton da Silva Vasconcelos, Francisco Tadeu Rantin, Ana Lúcia Kalinin
Matrinxã (Brycon amazonicus) is a great swimming performance teleost fish from the Amazon basin. However, the possible cardiac adaptations of this ability are still unknown. Therefore, the aim of the present work was to investigate the effects of prolonged exercise (EX group - 60days under 0.4BL·s(-1)) on ventricular contractility by (i) in-vitro analysis of contractility comparing the relative roles of sodium/calcium exchanger (NCX) and sarcoplasmic reticulum (SR) in the excitation-contraction (E-C) coupling and (ii) molecular analysis of NCX, sarcoplasmic reticulum Ca(2+) ATPase (SERCA2) and phospholamban (PLB) expression and quantification...
September 29, 2017: Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology
Jie Tong, Ying Qi, Xiangmiao Wang, Liyin Yu, Chang Su, Wenjun Xie, Jianbao Zhang
The mechanism by which cell shape regulates the function of the cell is one of the most important biological issues, but it remains unclear. Here, we investigated the effect of the regulation of cell shape on proliferation by using a micropatterning approach to confine MC3T3-E1 cells into specific shapes. Our results show that the proliferation rate for rectangle-, triangle-, square- and circle-shaped osteoblasts increased sequentially and was related to the nuclear shape index (NSI) but not the cell shape index (CSI)...
December 2017: Biochimica et Biophysica Acta
Jian Gao, Minmin Fan, Shuang Peng, Minxia Zhang, Gang Xiang, Xin Li, Wenjie Guo, Yang Sun, Xuefeng Wu, Xudong Wu, Guang Liang, Yan Shen, Qiang Xu
Triple-negative breast cancer (TNBC) has an aggressive phenotype and a poor prognosis owing to the high propensity for metastatic progression and the absence of specific targeted treatment. Here, we revealed that small-molecule RL71 targeting sarco/endoplasmic reticulum calcium-ATPase 2 (SERCA2) exhibited potent anti-cancer activity on all TNBC cells tested. Apart from apoptosis induction, RL71 triggered excessive autophagic cell death, the main contributor to RL71-induced TNBC cell death. RL71 augmented the release of Ca(2+) from the endoplasmic reticulum (ER) into the cytosol by inhibiting SERCA2 activity...
September 14, 2017: Cell Death & Disease
Yao Wang, Su Wei, Yi-Lu Wang, Miao Liu, Man Shang, Qi Zhang, Yan-Na Wu, Ming-Lin Liu, Jun-Qiu Song, Yan-Xia Liu
OBJECTIVE: To investigate the effects of circulating microvesicles derived from myocardial ischemia (I-MVs) on apoptosis in myocardial ischemia/reperfusion (I/R) injury in rats. METHODS: I-MVs from rats undergoing myocardial left anterior descending (LAD) coronary artery ligation were isolated by ultracentrifugation from circulating blood and characterized by flow cytometry. I-MVs were administered intravenously (4.8 mg/kg) at 5 min before reperfusion procedure in I/R injury model which was induced by 30-min of ischemia and 120-min of reperfusion of LAD in rats...
August 15, 2017: Oncotarget
Jorge Fragoso-Medina, Gabriela Rodriguez, Angel Zarain-Herzberg
The cardiac sarco/endoplasmic reticulum Ca(2+)-ATPase-2a (SERCA2a) is vital for the correct handling of calcium concentration in cardiomyocytes. Recent studies showed that the induction of endoplasmic reticulum (ER) stress (ERS) with the SERCA2 inhibitor Thapsigargin (Tg) increases the mRNA and protein levels of SERCA2a. The SERCA2 gene promoter contains an ERS response element (ERSE) at position -78 bp that is conserved among species and might transcriptionally regulate SERCA2 gene expression. However, its involvement in SERCA2 basal and calcium-mediated transcriptional activation has not been elucidated...
September 7, 2017: Molecular and Cellular Biochemistry
Vikas Kumar, Kumar A Aneesh, K Kshemada, Kumar G S Ajith, Raj S S Binil, Neha Deora, G Sanjay, A Jaleel, T S Muraleedharan, E M Anandan, R S Mony, M S Valiathan, Kumar T R Santhosh, C C Kartha
We evaluated the cardioprotective effect of Amalaki Rasayana (AR), a rejuvenating Ayurvedic drug prepared from Phyllanthus emblica fruits in the reversal of remodeling changes in pressure overload left ventricular cardiac hypertrophy (LVH) and age-associated cardiac dysfunction in male Wistar rats. Six groups (aging groups) of 3 months old animals were given either AR or ghee and honey (GH) orally; seventh group was untreated. Ascending aorta was constricted using titanium clips in 3 months old rats (N = 24; AC groups) and after 6 months, AR or GH was given for further 12 months to two groups; one group was untreated...
August 17, 2017: Scientific Reports
Li Nie, Xin-Lu Yuan, Ke-Tao Jiang, Yu-Hui Jiang, Jin Yuan, Lan Luo, Shi-Wei Cui, Cheng Sun
Salsalate plays beneficial roles for ameliorating hyperglycemia and dyslipidemia in type 2 diabetes patients, but the underlying mechanisms are still poorly understood. In this study, by administering salsalate to mice fed with high fat diet and examining how salsalate rectifies metabolic dysfunction in these obese mice, we found that salsalate stimulated body temperature and attenuated body weight gain without affecting food intake. Our results showed that salsalate application decreased lipid accumulation in liver and epididymal white adipose tissue (eWAT), inhibited hepatic gluconeogenesis and improved insulin signaling transduction in eWAT...
September 2017: EBioMedicine
Jianyou Zhang, Hui Liu, Shitong Li, Jin Wu, Jianhong Sun
The present study aimed to investigate the effects of acute sepsis on diaphragm contractility and relaxation, via examining the Ca2+‑uptake function of sarco/endoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA), and the protein levels of SERCA1, SERCA2 and the ryanodine receptor (RyR) of the sarcoplasmic reticulum (SR). A sepsis rat model was established through cecal ligation and puncture (CLP). A total of 6 and 12 h following CLP, the isometric contractile and relaxation parameters of the diaphragm were measured...
October 2017: Molecular Medicine Reports
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