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Bang M.-L.,Institute of Genetic and Biomedical Research | Gu Y.,University of California at San Diego | Dalton N.D.,University of California at San Diego | Peterson K.L.,University of California at San Diego | And 3 more authors.

Ankrd1/CARP, Ankrd2/Arpp, and Ankrd23/DARP belong to a family of stress inducible ankyrin repeat proteins expressed in striated muscle (MARPs). The MARPs are homologous in structure and localized in the nucleus where they negatively regulate gene expression as well as in the sarcomeric I-band, where they are thought to be involved in mechanosensing. Together with their strong induction during cardiac disease and the identification of causative Ankrd1 gene mutations in cardiomyopathy patients, this suggests their important roles in cardiac development, function, and disease. To determine the functional role of MARPs in vivo, we studied knockout (KO) mice of each of the three family members. Single KO mice were viable and had no apparent cardiac phenotype. We therefore hypothesized that the three highly homologous MARP proteins may have redundant functions in the heart and studied double and triple MARP KO mice. Unexpectedly, MARP triple KO mice were viable and had normal cardiac function both at basal levels and in response to mechanical pressure overload induced by transverse aortic constriction as assessed by echocardiography and hemodynamic studies. Thus, CARP, Ankrd2, and DARP are not essential for normal cardiac development and function at basal conditions and in response to mechanical pressure overload. © 2014 Bang et al. Source

Elia L.,Humanitas Clinical and Research Center | Elia L.,Institute of Genetic and Biomedical Research | Condorelli G.,Humanitas Clinical and Research Center | Condorelli G.,Institute of Genetic and Biomedical Research | Condorelli G.,University of Milan
Journal of Molecular and Cellular Cardiology

Next-generation sequencing has greatly improved our knowledge of the mammalian transcriptome, identifying thousands of non-coding RNAs (ncRNAs), which are RNAs that rather than translate for proteins, have regulatory functions. Perhaps unsurprisingly, dysregulation of individual ncRNAs has been associated with the development of pathologies, including of the cardiovascular system. The best-characterized group of ncRNAs is represented by the short, highly conserved RNAs named microRNAs (miRNAs). This ncRNA species, which principally exerts an inhibitory action on gene expression, has been implicated in many cardiovascular diseases. Unfortunately, the complexity of action of other types of ncRNA, such as long ncRNAs, has somewhat hampered the study of their role in cardiovascular pathologies. A detailed characterization of the mechanism of action of these different ncRNA species would be conducive to a better understanding of the cellular processes underlying cardiovascular disease and may lead to the development of innovative therapeutic strategies. Here, we give an overview of the current knowledge on the function of ncRNAs and their roles in cardiovascular disease development, concentrating mainly on microRNAs and long ncRNAs. © 2015 Elsevier Ltd. Source

Castaldi A.,Institute of Genetic and Biomedical Research | Castaldi A.,University of Milan Bicocca | Zaglia T.,Venetian Institute of Molecular Medicine | Zaglia T.,University of Padua | And 21 more authors.
Circulation Research

RATIONALE:: The sympathetic nervous system plays a fundamental role in the regulation of myocardial function. During chronic pressure overload, overactivation of the sympathetic nervous system induces the release of catecholamines, which activate β-adrenergic receptors in cardiomyocytes and lead to increased heart rate and cardiac contractility. However, chronic stimulation of β-adrenergic receptors leads to impaired cardiac function, and β-blockers are widely used as therapeutic agents for the treatment of cardiac disease. MicroRNA-133 (miR-133) is highly expressed in the myocardium and is involved in controlling cardiac function through regulation of messenger RNA translation/stability. OBJECTIVE:: To determine whether miR-133 affects β-adrenergic receptor signaling during progression to heart failure. METHODS AND RESULTS:: Based on bioinformatic analysis, β1-adrenergic receptor (β1AR) and other components of the β1AR signal transduction cascade, including adenylate cyclase VI and the catalytic subunit of the cAMP-dependent protein kinase A, were predicted as direct targets of miR-133 and subsequently validated by experimental studies. Consistently, cAMP accumulation and activation of downstream targets were repressed by miR-133 overexpression in both neonatal and adult cardiomyocytes following selective β1AR stimulation. Furthermore, gain-of-function and loss-of-function studies of miR-133 revealed its role in counteracting the deleterious apoptotic effects caused by chronic β1AR stimulation. This was confirmed in vivo using a novel cardiac-specific TetON-miR-133 inducible transgenic mouse model. When subjected to transaortic constriction, TetON-miR-133 inducible transgenic mice maintained cardiac performance and showed attenuated apoptosis and reduced fibrosis compared with control mice. CONCLUSIONS:: miR-133 controls multiple components of the β1AR transduction cascade and is cardioprotective during heart failure. © 2014 American Heart Association, Inc. Source

Marrella V.,Institute of Genetic and Biomedical Research | Maina V.,Institute of Genetic and Biomedical Research | Villa A.,Institute of Genetic and Biomedical Research
Current Opinion in Allergy and Clinical Immunology

Purpose of Review: During the past decade, easy access to sequence analyses has allowed us to increase our understanding of the pathogenesis of severe combined immunodeficiencies. Here, we describe the expanding clinical and immunological spectrum associated with Omenn syndrome phenotype. In particular, we review the cellular and molecular mechanisms involved in the pathophysiology of classical Omenn syndrome due to the recombination activating gene (RAG) defects and of a new subgroup of Omenn-like disorders. Recent Findings: Different types of mutations are associated with the Omenn phenotype characterized by skin erythroderma, oligoclonal-activated T cells and elevated IgE in the absence of circulating B cells. Extensive studies conducted over the last few years have allowed the definition of the classical form of Omenn syndrome due to hypomorphic defects in genes involved in V(D)J recombination, mainly RAG genes, and Omenn-like features associated with mutations in genes involved in the maturation steps of lymphoid cells other than V(D)J recombination. Moreover, an increasing number of diseases other than those due to V(D)J recombination defects develop Omenn signs. Summary: Impaired but not abolished V(D)J recombination process leads to the generation of a few T cells which expand in the periphery, infiltrate target organs such as skin and gut, resulting in severe erythroderma and colitis, both typical signs of Omenn syndrome. Extensive molecular studies now demonstrate that genes other than V(D)J molecules have a role in the pathogenesis of this disease, supporting the evidence that Omenn defines an inflammatory condition associated with various genetic defects. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

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