Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies

Abstract The Ras family of small Guanosine Triphosphate (GTP)-binding proteins (G proteins) represents one of the main components of intracellular signal transduction required for normal cardiac growth, but is also critically involved in the development of cardiac hypertrophy and heart failure. The...

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Autores principales:	Ramos-Kuri,Manuel, Meka,Sri Harika, Salamanca-Buentello,Fabio, Hajjar,Roger J., Lipskaia,Larissa, Chemaly,Elie R.
Lenguaje:	English
Publicado:	Sociedad de Biología de Chile 2021
Materias:	Ras-opathies H-Ras gene K-Ras gene Ras pathway Physiological hypertrophy Pathological hypertrophy MAP kinase Calcineurin
Acceso en línea:	http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-97602021000100503
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spelling	oai:scielo:S0716-976020210001005032021-09-30Molecules linked to Ras signaling as therapeutic targets in cardiac pathologiesRamos-Kuri,ManuelMeka,Sri HarikaSalamanca-Buentello,FabioHajjar,Roger J.Lipskaia,LarissaChemaly,Elie R. Ras-opathies H-Ras gene K-Ras gene Ras pathway Physiological hypertrophy Pathological hypertrophy MAP kinase Calcineurin Abstract The Ras family of small Guanosine Triphosphate (GTP)-binding proteins (G proteins) represents one of the main components of intracellular signal transduction required for normal cardiac growth, but is also critically involved in the development of cardiac hypertrophy and heart failure. The present review provides an update on the role of the H-, K- and N-Ras genes and their related pathways in cardiac diseases. We focus on cardiac hypertrophy and heart failure, where Ras has been studied the most. We also review other cardiac diseases, like genetic disorders related to Ras. The scope of the review extends from fundamental concepts to therapeutic applications. Although the three Ras genes have a nearly identical primary structure, there are important functional differences between them: H-Ras mainly regulates cardiomyocyte size, whereas K-Ras regulates cardiomyocyte proliferation. N-Ras is the least studied in cardiac cells and is less associated to cardiac defects. Clinically, oncogenic H-Ras causes Costello syndrome and facio-cutaneous-skeletal syndromes with hypertrophic cardiomyopathy and arrhythmias. On the other hand, oncogenic K-Ras and alterations of other genes of the Ras-Mitogen-Activated Protein Kinase (MAPK) pathway, like Raf, cause Noonan syndrome and cardio-facio-cutaneous syndromes characterized by cardiac hypertrophy and septal defects. We further review the modulation by Ras of key signaling pathways in the cardiomyocyte, including: (i) the classical Ras-Raf-MAPK pathway, which leads to a more physiological form of cardiac hypertrophy; as well as other pathways associated with pathological cardiac hypertrophy, like (ii) The SAPK (stress activated protein kinase) pathways p38 and JNK; and (iii) The alternative pathway Raf-Calcineurin-Nuclear Factor of Activated T cells (NFAT). Genetic alterations of Ras isoforms or of genes in the Ras-MAPK pathway result in Ras-opathies, conditions frequently associated with cardiac hypertrophy or septal defects among other cardiac diseases. Several studies underline the potential role of H- and K-Ras as a hinge between physiological and pathological cardiac hypertrophy, and as potential therapeutic targets in cardiac hypertrophy and failure. Highlights - The Ras (Rat Sarcoma) gene family is a group of small G proteins - Ras is regulated by growth factors and neurohormones affecting cardiomyocyte growth and hypertrophy - Ras directly affects cardiomyocyte physiological and pathological hypertrophy - Genetic alterations of Ras and its pathways result in various cardiac phenotypes? - Ras and its pathway are differentially regulated in acquired heart disease - Ras modulation is a promising therapeutic target in various cardiac conditions.info:eu-repo/semantics/openAccessSociedad de Biología de ChileBiological Research v.54 20212021-01-01text/htmlhttp://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-97602021000100503en10.1186/s40659-021-00342-6
institution	Scielo Chile
collection	Scielo Chile
language	English
topic	Ras-opathies H-Ras gene K-Ras gene Ras pathway Physiological hypertrophy Pathological hypertrophy MAP kinase Calcineurin
spellingShingle	Ras-opathies H-Ras gene K-Ras gene Ras pathway Physiological hypertrophy Pathological hypertrophy MAP kinase Calcineurin Ramos-Kuri,Manuel Meka,Sri Harika Salamanca-Buentello,Fabio Hajjar,Roger J. Lipskaia,Larissa Chemaly,Elie R. Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies
description	Abstract The Ras family of small Guanosine Triphosphate (GTP)-binding proteins (G proteins) represents one of the main components of intracellular signal transduction required for normal cardiac growth, but is also critically involved in the development of cardiac hypertrophy and heart failure. The present review provides an update on the role of the H-, K- and N-Ras genes and their related pathways in cardiac diseases. We focus on cardiac hypertrophy and heart failure, where Ras has been studied the most. We also review other cardiac diseases, like genetic disorders related to Ras. The scope of the review extends from fundamental concepts to therapeutic applications. Although the three Ras genes have a nearly identical primary structure, there are important functional differences between them: H-Ras mainly regulates cardiomyocyte size, whereas K-Ras regulates cardiomyocyte proliferation. N-Ras is the least studied in cardiac cells and is less associated to cardiac defects. Clinically, oncogenic H-Ras causes Costello syndrome and facio-cutaneous-skeletal syndromes with hypertrophic cardiomyopathy and arrhythmias. On the other hand, oncogenic K-Ras and alterations of other genes of the Ras-Mitogen-Activated Protein Kinase (MAPK) pathway, like Raf, cause Noonan syndrome and cardio-facio-cutaneous syndromes characterized by cardiac hypertrophy and septal defects. We further review the modulation by Ras of key signaling pathways in the cardiomyocyte, including: (i) the classical Ras-Raf-MAPK pathway, which leads to a more physiological form of cardiac hypertrophy; as well as other pathways associated with pathological cardiac hypertrophy, like (ii) The SAPK (stress activated protein kinase) pathways p38 and JNK; and (iii) The alternative pathway Raf-Calcineurin-Nuclear Factor of Activated T cells (NFAT). Genetic alterations of Ras isoforms or of genes in the Ras-MAPK pathway result in Ras-opathies, conditions frequently associated with cardiac hypertrophy or septal defects among other cardiac diseases. Several studies underline the potential role of H- and K-Ras as a hinge between physiological and pathological cardiac hypertrophy, and as potential therapeutic targets in cardiac hypertrophy and failure. Highlights - The Ras (Rat Sarcoma) gene family is a group of small G proteins - Ras is regulated by growth factors and neurohormones affecting cardiomyocyte growth and hypertrophy - Ras directly affects cardiomyocyte physiological and pathological hypertrophy - Genetic alterations of Ras and its pathways result in various cardiac phenotypes? - Ras and its pathway are differentially regulated in acquired heart disease - Ras modulation is a promising therapeutic target in various cardiac conditions.
author	Ramos-Kuri,Manuel Meka,Sri Harika Salamanca-Buentello,Fabio Hajjar,Roger J. Lipskaia,Larissa Chemaly,Elie R.
author_facet	Ramos-Kuri,Manuel Meka,Sri Harika Salamanca-Buentello,Fabio Hajjar,Roger J. Lipskaia,Larissa Chemaly,Elie R.
author_sort	Ramos-Kuri,Manuel
title	Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies
title_short	Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies
title_full	Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies
title_fullStr	Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies
title_full_unstemmed	Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies
title_sort	molecules linked to ras signaling as therapeutic targets in cardiac pathologies
publisher	Sociedad de Biología de Chile
publishDate	2021
url	http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-97602021000100503
work_keys_str_mv	AT ramoskurimanuel moleculeslinkedtorassignalingastherapeutictargetsincardiacpathologies AT mekasriharika moleculeslinkedtorassignalingastherapeutictargetsincardiacpathologies AT salamancabuentellofabio moleculeslinkedtorassignalingastherapeutictargetsincardiacpathologies AT hajjarrogerj moleculeslinkedtorassignalingastherapeutictargetsincardiacpathologies AT lipskaialarissa moleculeslinkedtorassignalingastherapeutictargetsincardiacpathologies AT chemalyelier moleculeslinkedtorassignalingastherapeutictargetsincardiacpathologies
_version_	1718441621070020608

Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies

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