Laboratory of Molecular Cardiology
Laboratory of Molecular Cardiology
Moccia F.,University of Pavia |
Zuccolo E.,University of Pavia |
Soda T.,University of Pavia |
Tanzi F.,University of Pavia |
And 5 more authors.
Frontiers in Cellular Neuroscience | Year: 2015
Stimi and Orail are ubiquitous proteins that have long been known to mediate Ca2+ release-activated Ca2+ (CRAC) current (Icrac) and store-operated Ca2+ entry (SOCE) only in non-excitable cells. SOCE is activated following the depletion of the endogenous Ca2+ stores, which are mainly located within the endoplasmic reticulum (ER), to replete the intracellular Ca2+ reservoir and engage specific Ca2+-dependent processes, such as proliferation, migration, cytoskeletal remodeling, and gene expression. Their paralogs, Stim2, Orai2 and Orai3, support SOCE in heterologous expression systems, but their physiological role is still obscure. Ca2 + inflow in neurons has long been exclusively ascribed to voltage-operated and receptor-operated channels. Nevertheless, recent work has unveiled that Stim1-2 and Orai1-2, but not Orai3, proteins are also expressed and mediate SOCE in neurons. Herein, we survey current knowledge about the neuronal distribution of Stim and Orai proteins in rodent and human brains; we further discuss that Orai2 is the main pore-forming subunit of CRAC channels in central neurons, in which it may be activated by either Stim1 or Stim2 depending on species, brain region and physiological stimuli. We examine the functions regulated by SOCE in neurons, where this pathway is activated under resting conditions to refill the ER, control spinogenesis and regulate gene transcription. Besides, we highlighted the possibility that SOCE also controls neuronal excitation and regulate synaptic plasticity. Finally, we evaluate the involvement of Stim and Orai proteins in severe neurodegenerative and neurological disorders, such as Alzheimer's disease and epilepsy. © 2015, Frontiers Research Foundation. All rights reserved.
Jin H.,Peking University |
Liu A.D.,Linköping University |
Holmberg L.,Linköping University |
Zhao M.,Peking University |
And 7 more authors.
International Journal of Molecular Sciences | Year: 2013
The authors investigated the regulatory effects of sulfur dioxide (SO2) on myocardial injury induced by isopropylarterenol (ISO) hydrochloride and its mechanisms. Wistar rats were divided into four groups: control group, ISO group, ISO plus SO2 group, and SO2 only group. Cardiac function was measured and cardiomyocyte apoptosis was detected. Bcl-2, bax and cytochrome c (cytc) expressions, and caspase-9 and caspase-3 activities in the left ventricular tissues were examined in the rats. The opening status of myocardial mitochondrial permeability transition pore (MPTP) and membrane potential were analyzed. The results showed that ISO-treated rats developed heart dysfunction and cardiac injury. Furthermore, cardiomyocyte apoptosis in the left ventricular tissues was augmented, left ventricular tissue bcl-2 expression was down-regulated, bax expression was up-regulated, mitochondrial membrane potential was significantly reduced, MPTP opened, cytc release from mitochondrion into cytoplasm was significantly increased, and both caspase-9 and caspase-3 activities were increased. Administration of an SO2 donor, however, markedly improved heart function and relieved myocardial injury of the ISO-treated rats; it lessened cardiomyocyte apoptosis, up-regulated myocardial bcl-2, down-regulated bax expression, stimulated mitochondrial membrane potential, closed MPTP, and reduced cytc release as well as caspase-9 and caspase-3 activities in the left ventricular tissue. Hence, SO2 attenuated myocardial injury in association with the inhibition of apoptosis in myocardial tissues, and the bcl-2/cytc/caspase-9/caspase-3 pathway was possibly involved in this process. © 2013 by the authors; licensee MDPI, Basel, Switzerland.
Bazan H.A.,Section of Vascular and Endovascular Surgery |
Hatfield S.A.,Tulane Heart and Vascular Institute |
O'Malley C.B.,Laboratory of Molecular Cardiology |
Brooks A.J.,Section of Vascular and Endovascular Surgery |
And 3 more authors.
Stroke | Year: 2015
Background and Purpose-Atherosclerotic plaque vulnerability is accompanied by changes in the molecular and cellular function in the plaque shoulder, including a decrease in vascular smooth muscle cell proliferation. We aimed to determine whether the expression of 3 miRNAs that regulate vascular smooth muscle cell proliferation (miR-145, miR-221, and miR-222) is altered with plaque rupture, suggesting a role in regulating plaque stability. Methods-miRNAs were measured in the plaque shoulder of carotid plaques obtained from patients undergoing carotid endarterectomy (CEA) for 3 distinct clinical scenarios: (1) patients without previous neurological events but high-grade carotid stenosis (asymptomatic), (2) patients with an acute neurological event within 5 days of the CEA (urgent), and (3) patients undergoing CEA>5 days after a neurological event (symptomatic). Results-Mean time from plaque rupture event to CEA was 2.4 days in the urgent group. The urgent group exhibited a significant decrease in miR-221 and miR-222 expression in the plaque shoulder, whereas no significant differences were seen in miR-145 across the 3 groups. Regression analysis demonstrated a significant correlation between time from the neurological event to CEA and increasing miR-221 and miR-222, but not miR-145. mRNA encoding p27Kip1, a target of miR-221 and miR-222 that inhibits vascular smooth muscle cell proliferation, was increased in the urgent group. Conclusions-Atherosclerotic plaque rupture is accompanied by a loss of miR-221 and miR-222 and an increase in p27Kip1 mRNA expression in the plaque shoulder, suggesting an association between these miRNAs and atherosclerotic plaque stability. © 2015 American Heart Association, Inc.
Latronico M.V.G.,Laboratory of Molecular Cardiology |
Condorelli G.,Laboratory of Molecular Cardiology |
Condorelli G.,National Research Council Italy
Current Drug Targets | Year: 2010
Heart ion-channel function and expression are continuously being regulated on the basis of the hemodynamic state of the cardiovascular system, the neurohumoral milieu and the properties of the ongoing ionic fluxes. These homeostatic forces act through multiple mechanisms at transcriptional, translational and post-translational levels. Of clinical importance is the fact that with adverse stress these regulatory mechanisms can produce arrhythmogenic channel remodelling. Although a great deal is known about the functionality of ion channels and the generation of the action potential, much less is known about the underlying controlling mechanisms and how these become derailed during disease. microRNA-mediated posttranscriptional control is a very recent addition to cardiovascular biology. Here, we outline discoveries pertaining to these new regulators and how they might be involved in cardiac electrophysiology and pathology. © 2010 Bentham Science Publishers Ltd.
Iachettini S.,Laboratory of Muscle Histopathology and Molecular Biology |
Valaperta R.,Research Laboratories |
Valaperta R.,Service of Laboratory Medicine 1 Clinical |
Marchesi A.,University of Milan |
And 8 more authors.
European Journal of Histochemistry | Year: 2015
Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a CTG repeat expansion in 3’UTR of DMPK gene. This mutation causes accumulation of toxic RNA in nuclear foci leading to splicing misregulation of specific genes. In view of future clinical trials with antisense oligonucleotides in DM1 patients, it is important to set up sensitive and minimally-invasive tools to monitor the efficacy of treatments on skeletal muscle. A tibialis anterior (TA) muscle sample of about 60 mg was obtained from 5 DM1 patients and 5 healthy subjects through a needle biopsy. A fragment of about 40 mg was used for histological examination and a fragment of about 20 mg was used for biomolecular analysis. The TA fragments obtained with the minimally-invasive needle biopsy technique is enough to perform all the histopathological and biomolecular evaluations useful to monitor a clinical trial on DM1 patients. ©S. Iachettini et al., 2015.
Ma X.,Laboratory of Molecular Cardiology |
Adelstein R.S.,Laboratory of Molecular Cardiology
Bioarchitecture | Year: 2014
Three different genes each located on a different chromosome encode the heavy chains of nonmuscle myosin II in humans and mice. This review explores the functional consequences of the presence of three isoforms during embryonic development and beyond. The roles of the various isoforms in cell division, cell-cell adhesion, blood vessel formation and neuronal cell migration are addressed in animal models and at the cellular level. Particular emphasis is placed on the role of nonmuscle myosin II during cardiac and brain development, and during closure of the neural tube and body wall. Questions addressed include the consequences on organ development, of lowering or ablating a particular isoform as well as the effect of substituting one isoform for another, all in vivo. Finally the roles of the three isoforms in human diseases such as cancer as well as in syndromes affecting a variety of organs in humans are reviewed.
Holst A.G.,Copenhagen University |
Holst A.G.,Laboratory of Molecular Cardiology |
Liang B.,Copenhagen University |
Jespersen T.,Copenhagen University |
And 7 more authors.
Cardiology | Year: 2010
Mutations in the cardiac sodium channel encoded by the gene SCN5A can result in a wide array of phenotypes. We report a case of a young male with a novel SCN5A mutation (R121W) afflicted by sick sinus syndrome, progressive cardiac conduction disorder, atrial flutter and ventricular tachycardia. His father carried the same mutation, but had a milder phenotype, presenting with progressive cardiac conduction later in life. The mutation was found to result in a loss-of-function in the sodium current. In conclusion, the same SCN5A mutation can result in a wide array of clinical phenotypes and perhaps the spectrum of SCN5A loss-of-function associated disease entities should be viewed as one syndrome. © 2010 S. Karger AG, Basel.
Greco S.,Laboratory of Molecular Cardiology |
Gorospe M.,U.S. National Institute on Aging |
Martelli F.,Laboratory of Molecular Cardiology
Journal of Molecular and Cellular Cardiology | Year: 2015
Eukaryotic gene expression is tightly regulated transcriptionally and post-transcriptionally by a host of noncoding (nc)RNAs. The best-studied class of short ncRNAs, microRNAs, mainly repress gene expression post-transcriptionally. Long noncoding (lnc)RNAs, which comprise RNAs differing widely in length and function, can regulate gene transcription as well as post-transcriptional mRNA fate. Collectively, ncRNAs affect a broad range of age-related physiologic deteriorations and pathologies, including reduced cardiovascular vigor and age-associated cardiovascular disease. This review presents an update of our understanding of regulatory ncRNAs contributing to cardiovascular health and disease as a function of advancing age. We will discuss (1) regulatory ncRNAs that control aging-associated cardiovascular homeostasis and disease, (2) the concepts, approaches, and methodologies needed to study regulatory ncRNAs in cardiovascular aging and (3) the challenges and opportunities that age-associated regulatory ncRNAs present in cardiovascular physiology and pathology. This article is part of a Special Issue entitled "CV Aging". © 2015 Elsevier Ltd.
Kim K.K.,Laboratory of Molecular Cardiology |
Nam J.,U.S. National Institutes of Health |
Mukouyama Y.-S.,U.S. National Institutes of Health |
Kawamoto S.,Laboratory of Molecular Cardiology
Journal of Cell Biology | Year: 2013
Alternative premRNA splicing is a major mechanism to generate diversity of gene products. However, the biological roles of alternative splicing during development remain elusive. Here, we focus on a neuron-specific RNA-binding protein, Rbfox3, recently identified as the antigen of the widely used anti-NeuN antibody. siRNA-mediated loss-of-function studies using the developing chicken spinal cord revealed that Rbfox3 is required to promote neuronal differentiation of postmitotic neurons. Numb premRNA encoding a signaling adaptor protein was found to be a target of Rbfox3 action, and Rbfox3 repressed the inclusion of an alternative exon via binding to the conserved UGCAUG element in the upstream intron. Depleting a specific Numb splice isoform reproduced similar neuronal differentiation defects. Forced expression of the relevant Numb splice isoform was sufficient to rescue, in an isoform-specific manner, postmitotic neurons from defects in differentiation caused by Rbfox3 depletion. Thus, Rbfox3-dependent Numb alternative splicing plays an important role in the progression of neuronal differentiation during vertebrate development.