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.
Subject(s)
Humans , Heart Defects, Congenital , Noonan Syndrome , Signal Transduction , Cardiomegaly , Mitogen-Activated Protein Kinases/metabolism , MAP Kinase Signaling SystemABSTRACT
BACKGROUND: Long QT syndromes (LQTS) are inherited cardiac disorders caused by mutations in the genes that encode sodium or potassium transmembrane ion channel proteins. More than 200 mutations, in at least six genes, have been found in these patients. The Jervell and Lange-Nielsen (JLN) syndrome is the recessive form of the disease and is associated with deafness. Few families with JLN syndrome and genetic studies are reported in the literature. METHODS: The KCNQ1 (KvLQT1) gene in a Mexican family with Jervell-Lange-Nielsen long QT syndrome was analyzed using an automated sequence method. RESULTS: A missense mutation was found in the three affected individuals. This mutation is associated with complete loss of channel function. Correlation with the phenotype showed a prolonged QTc interval and deafness in the two siblings homozygous to the mutation. The mother, who was heterozygous for the mutation, also had prolonged QTc interval without deafness. The father and younger brother had normal QTc intervals. The mutation was not found in 50 healthy controls studied. CONCLUSIONS: We describe for the first time a mutation in the KCNQ1 gene in a Mexican family with JLN long QT syndrome. This mutation produces an amino acid change (Gly-Arg) at protein level at the 168 residue. This mutation has been previously reported in Caucasian families with LQTS.
Subject(s)
Adolescent , Child , Child, Preschool , Female , Humans , Male , Jervell-Lange Nielsen Syndrome , KCNQ1 Potassium Channel , Mutation, Missense , Mexico , PedigreeABSTRACT
The first step of the herpes virus infection is the attachment to heparan sulfate molecules on the cellular membrane. In order to improve the characterization of this phenomenon, we compared the inhibitory effect of six sulfated polyelectrolytes (PE): heparin, heparan, low molecular wight heparin, chondroitin, dextran and protamine on plaque formation by pseudorabies virus (PRV) were compared. The PE with the highest antiherpetic effect was heparin, followed by dextran sulfate. Heparan sulfate, which has been proposed as the initial receptor of herpes virus on the cell surface showed and effect 100-fold lower than heparin. Comparative inhibition curves of heparin and heparan sulfate against three herpes viruses: herpes simplex virus 1 (HSV-1), HSV 2 and PRV showed similar kinetics of inhibition of plaque formation, suggesting these viruses could share similar cell adsorption mechanisms