Pitychoutis PM, Sanoudou D, Papandreou M, Nasias D, Kouskou M, Tomlinson CR, Tsonis PA, Papadopoulou-Daifoti Z
. Forced swim test induces divergent global transcriptomic alterations in the hippocampus of high versus low novelty-seeker rats
. Hum GenomicsHum GenomicsHum Genomics. 2014;8:4.Abstract
BACKGROUND: Many neuropsychiatric disorders, including stress-related mood disorders, are complex multi-parametric syndromes. Susceptibility to stress and depression is individually different. The best animal model of individual differences that can be used to study the neurobiology of affect regards spontaneous reactions to novelty. Experimentally, when naive rats are exposed to the stress of a novel environment, they display a highly variable exploratory activity and are classified as high or low responders (HR or LR, respectively). Importantly, HR and LR rats do not seem to exhibit a substantial differentiation in relation to their 'depressive-like' status in the forced swim test (FST), a widely used animal model of 'behavioral despair'. In the present study, we investigated whether FST exposure would be accompanied by phenotype-dependent differences in hippocampal gene expression in HR and LR rats. RESULTS: HR and LR rats present a distinct behavioral pattern in the pre-test session but develop comparable depressive-like status in the second FST session. At 24 h following the second FST session, HR and LR rats (stressed and unstressed controls) were sacrificed and hippocampal samples were independently analyzed on whole rat genome Illumina arrays. Functional analysis into pathways and networks was performed using Ingenuity Pathway Analysis (IPA) software. Notably, hippocampal gene expression signatures between HR and LR rats were markedly divergent, despite their comparable depressive-like status in the FST. These molecular differences are reflected in both the extent of transcriptional remodeling (number of significantly changed genes) and the types of molecular pathways affected following FST exposure. A markedly higher number of genes (i.e., 2.28-fold) were statistically significantly changed following FST in LR rats, as compared to their HR counterparts. Notably, genes associated with neurogenesis and synaptic plasticity were induced in the hippocampus of LR rats in response to FST, whereas in HR rats, FST induced pathways directly or indirectly associated with induction of apoptotic mechanisms. CONCLUSIONS: The markedly divergent gene expression signatures exposed herein support the notion that the hippocampus of HR and LR rats undergoes distinct transcriptional remodeling in response to the same stress regimen, thus yielding a different FST-related 'endophenotype', despite the seemingly similar depressive-like phenotype.
Kalozoumi G, Yacoub M, Sanoudou D
. MicroRNAs in heart failure: Small molecules with major impact
. Glob Cardiol Sci PractGlob Cardiol Sci PractGlob Cardiol Sci Pract. 2014;2014:79-102.Abstract
MicroRNAs (miRNAs) have emerged as potent modulators of mammalian gene expression, thereby broadening the spectrum of molecular mechanisms orchestrating human physiological and pathological cellular functions. Growing evidence suggests that these small non-coding RNA molecules are pivotal regulators of cardiovascular development and disease. Importantly, multiple miRNAs have been specifically implicated in the onset and progression of heart failure, thus providing a new platform for battling this multi-faceted disease. This review introduces the basic concepts of miRNA biology, describes representative examples of miRNAs associated with multiple aspects of HF pathogenesis, and explores the prognostic, diagnostic and therapeutic potential of miRNAs in the cardiology clinic.
Valanti E, Tsompanidis A, Sanoudou D
. Pharmacogenomics in the development and characterization of atheroprotective drugs
. Methods Mol BiolMethods Mol BiolMethods Mol Biol. 2014;1175:259-300.Abstract
Atherosclerosis is the main cause of cardiovascular disease (CVD) and can lead to stroke, myocardial infarction, and death. The clinically available atheroprotective drugs aim mainly at reducing the levels of circulating low-density lipoprotein (LDL), increasing high-density lipoprotein (HDL), and attenuating inflammation. However, the cardiovascular risk remains high, along with morbidity, mortality, and incidence of adverse drug events. Pharmacogenomics is increasingly contributing towards the characterization of existing atheroprotective drugs, the evaluation of novel ones, and the identification of promising, unexplored therapeutic targets, at the global molecular pathway level. This chapter presents highlights of pharmacogenomics investigations and discoveries that have contributed towards the elucidation of pharmacological atheroprotection, while opening the way to new therapeutic approaches.
Vafiadaki E, Arvanitis DA, Papalouka V, Terzis G, Roumeliotis TI, Spengos K, Garbis SD, Manta P, Kranias EG, Sanoudou D
. Muscle lim protein isoform negatively regulates striated muscle actin dynamics and differentiation
. FEBS JFEBS JFEBS J. 2014;281:3261-79.Abstract
Muscle lim protein (MLP) has emerged as a critical regulator of striated muscle physiology and pathophysiology. Mutations in cysteine and glycine-rich protein 3 (CSRP3), the gene encoding MLP, have been directly associated with human cardiomyopathies, whereas aberrant expression patterns are reported in human cardiac and skeletal muscle diseases. Increasing evidence suggests that MLP has an important role in both myogenic differentiation and myocyte cytoarchitecture, although the full spectrum of its intracellular roles has not been delineated. We report the discovery of an alternative splice variant of MLP, designated as MLP-b, showing distinct expression in neuromuscular disease and direct roles in actin dynamics and muscle differentiation. This novel isoform originates by alternative splicing of exons 3 and 4. At the protein level, it contains the N-terminus first half LIM domain of MLP and a unique sequence of 22 amino acids. Physiologically, it is expressed during early differentiation, whereas its overexpression reduces C2C12 differentiation and myotube formation. This may be mediated through its inhibition of MLP/cofilin-2-mediated F-actin dynamics. In differentiated striated muscles, MLP-b localizes to the sarcomeres and binds directly to Z-disc components, including alpha-actinin, T-cap and MLP. The findings of the present study unveil a novel player in muscle physiology and pathophysiology that is implicated in myogenesis as a negative regulator of myotube formation, as well as in differentiated striated muscles as a contributor to sarcomeric integrity.