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Adam S Helms, Francisco J Alvarado, Jaime Yob, Vi T Tang, Francis Pagani, Mark W Russell, Héctor H Valdivia, Sharlene M Day
BACKGROUND: -Aberrant calcium signaling may contribute to arrhythmias and adverse remodeling in hypertrophic cardiomyopathy (HCM). Mutations in sarcomere genes may distinctly alter calcium handling pathways. METHODS: -We analyzed gene expression, protein levels, and functional assays for calcium regulatory pathways in human HCM surgical samples with (n=25) and without (n=10) sarcomere mutations compared with control hearts (n=8). RESULTS: -Gene expression and protein levels for calsequestrin, L-type calcium channel, sodium-calcium exchanger, phospholamban (PLN), calcineurin, and calcium/calmodulin-dependent protein kinase type II (CaMKII) were similar in HCM compared to controls...
September 29, 2016: Circulation
Maulilio John Kipanyula, Wahabu Hamisi Kimaro, Paul F Seke Etet
The ongoing epidemics of metabolic diseases and increase in the older population have increased the incidences of neurodegenerative diseases. Evidence from murine and cell line models has implicated calcineurin-nuclear factor of activated T-lymphocytes (NFAT) signaling pathway, a Ca(2+)/calmodulin-dependent major proinflammatory pathway, in the pathogenesis of these diseases. Neurotoxins such as amyloid-β, tau protein, and α-synuclein trigger abnormal calcineurin/NFAT signaling activities. Additionally increased activities of endogenous regulators of calcineurin like plasma membrane Ca(2+)-ATPase (PMCA) and regulator of calcineurin 1 (RCAN1) also cause neuronal and glial loss and related functional alterations, in neurodegenerative diseases, psychotic disorders, epilepsy, and traumatic brain and spinal cord injuries...
2016: Journal of Aging Research
Qian-Qian Lei, Gui-Qiu Hu, Wei Chen, Shui-Xing Yu, Shuai Qi, Chong-Tao Du, Jing-Min Gu, Tong-Jun Lin, Yong-Jun Yang
OBJECTIVE: RCAN1 (regulator of calcineurin 1) has been shown to be involved in various physiological and pathological processes. However, the biological implications of RCAN1 during gastrointestinal tract infection remain unclear. In this study, we tried to determine the role of RCAN1 in acute Salmonella infectious colitis. METHODS: Wild type and RCAN1-deficient mice or macrophages were used to characterize the impacts of RCAN1 on intestinal inflammation, inflammatory cytokines production, animal survival, and pathogen clearance following Salmonella challenge...
September 2016: Molecular Immunology
Ulrike Peters, Eleni Solominidou, Yüksel Korkmaz, Stefan Rüttermann, Astrid Klocke, Thomas Frank Flemmig, Thomas Beikler
Nuclear factor of activated T-cells (NFAT) and NF-kB pathway associated processes are involved in the pathogenesis of various inflammatory disorders, for example, periodontal disease. The activation of these pathways is controlled by the regulator of calcineurin 1 (RCAN1). The aim of this study was to elucidate the role of RCAN1 in periodontal disease. Healthy and inflamed periodontal tissues were analyzed by immunohistochemistry and immunofluorescence using specific rabbit polyclonal anti-RCAN1 antibodies...
2016: Mediators of Inflammation
Guodong Wang, Yilei Zhao, Shenpeng Liu, Jinling Jia, Tan Lu
Spinal cord injury (SCI) is a severe clinical problem worldwide. The pathogenesis of SCI is complicated and much is unknown. The current study was designed to investigate the possible role of regulator of calcineurin 1 (RCAN1) in SCI and to explore the possible molecular mechanisms. Rats were injected with LVshRNAi-RCAN1 and then contusion-induced SCI was established. We found that RCAN1 was significantly increased in spinal cord of rats with SCI. Knockdown of RCAN1 markedly facilitated the structural and functional recovery in the spinal cord, as illustrated by decrease of lesion volume and increase of Basso, Beattie, and Bresnahan (BBB) and combined behavioral score (CBS) scores...
June 23, 2016: Journal of Physiology and Biochemistry
Heshan Peiris, Michael D Duffield, Joao Fadista, Claire F Jessup, Vinder Kashmir, Amanda J Genders, Sean L McGee, Alyce M Martin, Madiha Saiedi, Nicholas Morton, Roderick Carter, Michael A Cousin, Alexandros C Kokotos, Nikolay Oskolkov, Petr Volkov, Tertius A Hough, Elizabeth M C Fisher, Victor L J Tybulewicz, Jorge Busciglio, Pinar E Coskun, Ann Becker, Pavel V Belichenko, William C Mobley, Michael T Ryan, Jeng Yie Chan, D Ross Laybutt, P Toby Coates, Sijun Yang, Charlotte Ling, Leif Groop, Melanie A Pritchard, Damien J Keating
Type 2 diabetes (T2D) is a complex metabolic disease associated with obesity, insulin resistance and hypoinsulinemia due to pancreatic β-cell dysfunction. Reduced mitochondrial function is thought to be central to β-cell dysfunction. Mitochondrial dysfunction and reduced insulin secretion are also observed in β-cells of humans with the most common human genetic disorder, Down syndrome (DS, Trisomy 21). To identify regions of chromosome 21 that may be associated with perturbed glucose homeostasis we profiled the glycaemic status of different DS mouse models...
May 2016: PLoS Genetics
Raul Sánchez-Lanzas, Beatriz Alvarez-Castelao, Teresa Bermejo, Teresa Ayuso, Teresa Tuñón, José G Castaño
Danon disease, a condition characterized by cardiomyopathy, myopathy, and intellectual disability, is caused by mutations in the LAMP-2 gene. Lamp-2A protein, generated by alternative splicing from the Lamp-2 pre-mRNA, is reported to be the lysosomal membrane receptor essential for the chaperone-mediated autophagic pathway (CMA) aimed to selective protein targeting and translocation into the lysosomal lumen for degradation. To study the relevance of Lamp-2 in protein degradation, a lymphoblastoid cell line was obtained by EBV transformation of B-cells from a Danon patient...
August 2016: Biochimica et Biophysica Acta
Yane Zhao, Jin Zhang, Xiaoyu Shi, Jing Li, Rui Wang, Ruiwen Song, Qun Wei, Huaibin Cai, Jing Luo
Calcineurin (CN) is a unique calcium/calmodulin (CaM)-activated serine/threonine phosphatase. To perform its diverse biological functions, CN communicates with many substrates and other proteins. In the physiological activation of T cells, CN acts through transcriptional factors belonging to the NFAT family and other transcriptional effectors. The classic immunosuppressive drug cyclosporin A (CsA) can bind to cyclophilin (CyP) and compete with CN for the NFAT LxVP motif. CsA has debilitating side effects, including nephrotoxicity, hypertension and tremor...
August 2016: Biochimie
Laurent Monassier, Estelle Ayme-Dietrich, Gaëlle Aubertin-Kirch, Atul Pathak
The mitochondrial permeability transition (mPTP) is a key feature of cardiac cell death in ischaemia-reperfusion injury (I/R). The mPTP blocker, cyclosporine A (CsA), has been shown to give protection against reperfusion-induced myocardial necrosis and troubles generated by acute coronary artery repermeabilization. Nevertheless, the results of the CIRCUS trial (Does Cyclosporine Improve Clinical Outcome in ST-Elevation Myocardial Infarction Patients) seem to go against this hypothesis. Pharmacological reasons linked to CsA pharmacokinetics and pharmacodynamics could be suggested...
April 2016: Fundamental & Clinical Pharmacology
Ami Patel, Naoya Yamashita, Maria Ascaño, Daniel Bodmer, Erica Boehm, Chantal Bodkin-Clarke, Yun Kyoung Ryu, Rejji Kuruvilla
Down syndrome is the most common chromosomal disorder affecting the nervous system in humans. To date, investigations of neural anomalies in Down syndrome have focused on the central nervous system, although dysfunction of the peripheral nervous system is a common manifestation. The molecular and cellular bases underlying peripheral abnormalities have remained undefined. Here, we report the developmental loss of sympathetic innervation in human Down syndrome organs and in a mouse model. We show that excess regulator of calcineurin 1 (RCAN1), an endogenous inhibitor of the calcineurin phosphatase that is triplicated in Down syndrome, impairs neurotrophic support of sympathetic neurons by inhibiting endocytosis of the nerve growth factor (NGF) receptor, TrkA...
December 14, 2015: Nature Communications
Helen Wong, Josien Levenga, Peter Cain, Beverly Rothermel, Eric Klann, Charles Hoeffer
Aging is the largest risk factor for Alzheimer's disease (AD). Patients with Down syndrome (DS) develop symptoms consistent with early-onset AD, suggesting that overexpression of chromosome 21 genes such as Regulator of Calcineurin 1 (RCAN1) plays a role in AD pathogenesis. RCAN1 levels are increased in the brain of DS and AD patients but also in the human brain with normal aging. RCAN1 has been implicated in several neuronal functions, but whether its increased expression is correlative or causal in the aging-related progression of AD remains elusive...
December 2015: Acta Neuropathologica
C Liu, L Zheng, H Wang, X Ran, H Liu, X Sun
Nuclear factor-κB (NF-κB) has a vital role in cell survival. Inhibition of NF-κB has been proven to be an efficient therapeutic pathway for various cancers. Activation of NF-κB is mainly through serine residues' phosphorylation of inhibitor of κBα (IκBα) by IKK complex. Phosphorylation at tyrosine 42 is an alternative pathway in regulation of IκBα and NF-κB signaling, though little is known about the underlying mechanism. Here we identified regulator of calcineurin 1 (RCAN1) as a novel endogenous inhibitor of NF-κB signaling pathway...
2015: Cell Death & Disease
Ramin Emrani Bidi, Amelie Rebillard, Dany Saligaut, Arlette Delamarche, Kelvin J A Davies, Josiane Cillard
Regulator of Calcineurin1 (RCAN1) controls the Sr/Thr phosphatase, Calcineurin. RCAN1 has never been studied in-vitro in myotubes following acute Electrical Pulse Stimulation (EPS) which recapitulates the physiological effect of exhaustive exercise and hyperglycemia (HG). 144 h differentiated C2C12 myotubes were treated either with high glucose (HG) at 15mM or kept as control for 48 h. The myotubes were subjected to EPS for 1second followed by 1second of pause for 90min. Two separate Non-EPS controls with and without HG were performed simultaneously...
October 2014: Free Radical Biology & Medicine
Eun Hye Lee, Seon Sook Kim, Seul Lee, Kwan-Hyuck Baek, Su Ryeon Seo
Pituitary adenylate cyclase-activating peptide (PACAP) is a neurotrophic peptide involved in a wide range of nervous functions, including development, differentiation, and survival, and various aspects of learning and memory. Here we report that PACAP induces the expression of regulator of calcineurin 1 (RCAN1, also known as DSCR1), which is abnormally expressed in the brains of Down syndrome patients. Increased RCAN1 expression is accompanied by activation of the PKA-cAMP response element-binding protein pathways...
August 21, 2015: Journal of Biological Chemistry
Ramin Emrani, Amélie Rébillard, Luz Lefeuvre, Arlette Gratas-Delamarche, Kelvin J A Davies, Josiane Cillard
The aim of this work was to study the regulation of the calcineurin antagonist regulator of calcineurin 1 (RCAN1) in rat skeletal muscles after exhaustive physical exercise, which is a physiological modulator of oxidative stress. Three skeletal muscles, namely extensor digitorum longus (EDL), gastrocnemius, and soleus, were investigated. Exhaustive exercise increased RCAN1-4 protein levels in EDL and gastrocnemius, but not in soleus. Protein oxidation as an index of oxidative stress was increased in EDL and gastrocnemius, but remained unchanged in soleus...
October 2015: Free Radical Biology & Medicine
G Jonatan Saenz, Rebeka Hovanessian, Andrew D Gisis, Rheem D Medh
Glucocorticoids (GCs) are known to induce apoptosis of leukemia cells via gene regulatory changes affecting key pro-and anti-apoptotic genes. Three genes previously implicated in GC-evoked apoptosis in the CEM human T-cell leukemia model, RCAN1, E4BP4 and BIM, were studied in a panel of human lymphoid and myeloid leukemia cell lines. Of the two RCAN1 transcripts, the synthetic GC Dexamethasone (Dex) selectively upregulates RCAN1-1, but not RCAN1-4, in GC-susceptible Sup-B15, RS4;11, Kasumi-1 cells but not in GC-resistant Sup T1 and Loucy cells...
August 7, 2015: Biochemical and Biophysical Research Communications
Juan E Camacho Londoño, Qinghai Tian, Karin Hammer, Laura Schröder, Julia Camacho Londoño, Jan C Reil, Tao He, Martin Oberhofer, Stefanie Mannebach, Ilka Mathar, Stephan E Philipp, Wiebke Tabellion, Frank Schweda, Alexander Dietrich, Lars Kaestner, Ulrich Laufs, Lutz Birnbaumer, Veit Flockerzi, Marc Freichel, Peter Lipp
AIMS: Pathological cardiac hypertrophy is a major predictor for the development of cardiac diseases. It is associated with chronic neurohumoral stimulation and with altered cardiac Ca(2+) signalling in cardiomyocytes. TRPC proteins form agonist-induced cation channels, but their functional role for Ca(2+) homeostasis in cardiomyocytes during fast cytosolic Ca(2+) cycling and neurohumoral stimulation leading to hypertrophy is unknown. METHODS AND RESULTS: In a systematic analysis of multiple knockout mice using fluorescence imaging of electrically paced adult ventricular cardiomyocytes and Mn(2+)-quench microfluorimetry, we identified a background Ca(2+) entry (BGCE) pathway that critically depends on TRPC1/C4 proteins but not others such as TRPC3/C6...
September 1, 2015: European Heart Journal
Miklós Kecskés, Griet Jacobs, Sara Kerselaers, Ninda Syam, Aurélie Menigoz, Peter Vangheluwe, Marc Freichel, Veit Flockerzi, Thomas Voets, Rudi Vennekens
Cardiac muscle adapts to hemodynamic stress by altering myocyte size and function, resulting in cardiac hypertrophy. Alteration in myocyte calcium homeostasis is known to be an initial signal in cardiac hypertrophy signaling. Transient receptor potential melastatin 4 protein (TRPM4) is a calcium-activated non-selective cation channel, which plays a role in regulating calcium influx and calcium-dependent cell functions in many cell types including cardiomyocytes. Selective deletion of TRPM4 from the heart muscle in mice resulted in an increased hypertrophic growth after chronic angiotensin (AngII) treatment, compared to WT mice...
2015: Basic Research in Cardiology
Hongyan Duan, Yongqiang Li, Lijie Yan, Haitao Yang, Jintao Wu, Peng Qian, Bing Li, Shanling Wang
Mitochondrial autophagy is an important adaptive stress response and can be modulated by various key molecules. A previous study found that the regulator of calcineurin 1-1L (Rcan1-1L) may regulate mitochondrial autophagy and cause mitochondria degradation in neurocytes. However, the effect of Rcan1-1L on cardiomyocytes has not been determined. In the present study, we aimed to investigate the role of Rcan1-1L in angiotensin II (Ang II)-exposed human cardiomyocytes. Above all, Human adult cardiac myocytes (HACMs) were exposed to 200nmol/L Ang II for 4 days...
July 1, 2015: Experimental Cell Research
Xiaoyong Li, Gang Wang, Yong An, Hongbo Li, Yonggang Li, Chun Wu
The pathogenesis of congenital heart disease (CHD) is unclear. There is a high incidence of CHD in Down syndrome, in which RCAN1 (regulator of calcineurin 1) overexpression is observed. However, whether RCAN1 plays an important role in non-syndromic CHD is unknown. This study investigates the relationship between sequence variations in the RCAN1 promoter and sporadic CHD. This was a case-control study in which the RCAN1 promoter was cloned and sequenced in 128 CHD patients (median age 1.1 year) and 150 normal controls (median age 3...
October 2015: Pediatric Cardiology
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