Bone Morphogenetic Protein Signaling Modulates Myocardin Transactivation of Cardiac Genes

Bone morphogenetic proteins (BMPs) play important roles in cardiovascular development. However, how BMP-signaling pathways regulate cardiac gene expression is less clear. We have previously identified myocardin as a cardiac and smooth muscle–specific transcriptional cofactor for serum response factor (SRF). Myocardin potently activates target gene expression by tethering with SRF bound to SRF-responsive elements, the CArG box. Here, we show that Smad1, an effector of the BMP-signaling pathway, synergistically activates myocardin-dependent cardiac gene expression. Interestingly, the CArG box is necessary and sufficient to mediate such synergy, whereas no obvious Smad-binding element appears to be involved. Consistent with their functional interaction, we find that myocardin and Smad1 proteins interact directly. Furthermore, myocardin protein levels were dramatically increased by BMP-2 treatment in cardiomyocytes. These findings suggest myocardin participates in a BMP signaling–dependent cardiac gene transcriptional program

MicroRNAs 1, 133, and 206: Critical factors of skeletal and cardiac muscle development, function, and disease

microRNAs (miRNAs) are a class of highly conserved small non-coding RNAs that negatively regulate gene expression post-transcriptionally. miRNAs are known to mediate myriad cell processes, including proliferation, differentiation, and apoptosis. With more than 600 miRNAs identified in humans, it is generally believed that many miRNAs function through simultaneously inhibiting multiple regulatory mRNA targets, suggesting that miRNAs participate in regulating the expression of many, if not all, genes. While many miRNAs are expressed ubiquitously, some are expressed in a tissue specific manner. The muscle specific miR-1, miR-133 and miR-206 are perhaps the most studied and best characterized miRNAs to date. Many studies demonstrate that these miRNAs are necessary for proper skeletal and cardiac muscle development and function, and have a profound influence on multiple myopathies, such as hypertrophy, dystrophy, and conduction defects

Evolving molecular diagnostics for familial cardiomyopathies: at the heart of it all

Cardiomyopathies are an important and heterogeneous group of common cardiac diseases. An increasing number of cardiomyopathies are now recognized to have familial forms, which result from single-gene mutations that render a Mendelian inheritance pattern, including hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy and left ventricular noncompaction cardiomyopathy. Recently, clinical genetic tests for familial cardiomyopathies have become available for clinicians evaluating and treating patients with these diseases, making it necessary to understand the current progress and challenges in cardiomyopathy genetics and diagnostics. In this review, we summarize the genetic basis of selected cardiomyopathies, describe the clinical utility of genetic testing for cardiomyopathies and outline the current challenges and emerging developments

miR-155 Inhibits Expression of the MEF2A Protein to Repress Skeletal Muscle Differentiation

microRNAs (miRNAs) are 21–23-nucleotide non-coding RNAs. It has become more and more evident that this class of small RNAs plays critical roles in the regulation of gene expression at the post-transcriptional level. MEF2A is a member of the MEF2 (myogenic enhancer factor 2) family of transcription factors. Prior report showed that the 3′-untranslated region (3′-UTR) of the Mef2A gene mediated its repression; however, the molecular mechanism underlying this intriguing observation was unknown. Here, we report that MEF2A is repressed by miRNAs. We identify miR-155 as one of the primary miRNAs that significantly represses the expression of MEF2A. We show that knockdown of the Mef2A gene by siRNA impairs myoblast differentiation. Similarly, overexpression of miR-155 leads to the repression of endogenous MEF2A expression and the inhibition of myoblast differentiation. Most importantly, reintroduction of MEF2A in miR-155 overexpressed myoblasts was able to partially rescue the miR-155-induced myoblast differentiation defect. Our data therefore establish miR-155 as an important regulator of MEF2A expression and uncover its function in muscle gene expression and myogenic differentiation

A density-temperature description of the outer electron radiation belt during geomagnetic storms

Bi-Maxwellian fits are made to energetic-electron flux measurements from seven satellites in geosynchronous orbit, yielding a number density (n) and temperature (T) description of the outer electron radiation belt. For 54.5 spacecraft years of measurements the median value of n is 3.7 × 10−4 cm−3, and the median value of T is 148 keV. General statistical properties of n, T, and the 1.1–1.5 MeV flux F are investigated, including local-time and solar-cycle dependencies. Using superposed-epoch analysis where the zero epoch is convection onset, the evolution of the outer electron radiation belt through high-speed-stream-driven storms is investigated. The number-density decay during the calm before the storm, relativistic-electron dropouts and recoveries, and the heating of the outer electron radiation belt during storms are analyzed. Using four different “triggers” (sudden storm commencement (SSC), southward interplanetary magnetic field (IMF) portions of coronal mass ejection (CME) sheaths, southward-IMF portions of magnetic clouds, and minimum Dst) a selection of CME-driven storms are analyzed with superposed-epoch techniques. For CME-driven storms, only a very modest density decay prior to storm onset is found. In addition, the compression of the outer electron radiation belt at the time of SSC is analyzed, the number-density increase and temperature decrease during storm main phase are characterized, and the increase in density and temperature during storm recovery phase is determined. During the different phases of storms, changes in the flux are sometimes in response to changes in the temperature, sometimes to changes in the number density, and sometimes to changes in both. Differences are found between the density-temperature and flux descriptions, and it is concluded that more information is available using the density-temperature description

The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation

Understanding the molecular mechanisms that regulate cellular proliferation and differentiation is a central theme of developmental biology. MicroRNAs (miRNAs) are a class of regulatory RNAs of ~22 nucleotides that post-transcriptionally regulate gene expression1,2. Increasing evidence points to the potential role of miRNAs in various biological processes3–8. Here we show that miRNA-1 (miR-1) and miRNA-133 (miR-133), which are clustered on the same chromosomal loci, are transcribed together in a tissue-specific manner during development. miR-1 and miR-133 have distinct roles in modulating skeletal muscle proliferation and differentiation in cultured myoblasts in vitro and in Xenopus laevis embryos in vivo. miR-1 promotes myogenesis by targeting histone deacetylase 4 (HDAC4), a transcriptional repressor of muscle gene expression. By contrast, miR-133 enhances myoblast proliferation by repressing serum response factor (SRF). Our results show that two mature miRNAs, derived from the same miRNA polycistron and transcribed together, can carry out distinct biological functions. Together, our studies suggest a molecular mechanism in which miRNAs participate in transcriptional circuits that control skeletal muscle gene expression and embryonic development

Expression of microRNAs is dynamically regulated during cardiomyocyte hypertrophy

MicroRNAs (miRNAs) are a recently discovered class of ∼22-nucleotide regulatory RNAs that post-transcriptionally regulate gene expression. We have recently demonstrated that muscle-specific miRNAs miR-1 and -133 play an important role in modulating muscle proliferation and differentiation. Here, we investigate the involvement of miRNAs in cardiac hypertrophy. We analyzed the global expression of miRNAs in agonist-induced hypertrophic cardiomyocytes as well as in pressure overload-induced hypertrophic hearts and found the miRNA expression profile altered in those hypertrophic conditions. We further show that inhibition of endogenous miR-21 or -18b augments hypertrophic growth. Conversely, introduction of functional miR-21 or -18b into cardiomyocytes represses myocyte hypertrophy. Together, our studies point to miRNAs as critical regulators of cardiac hypertrophy

Common MicroRNA Signatures in Cardiac Hypertrophic and Atrophic Remodeling Induced by Changes in Hemodynamic Load

BACKGROUND: Mechanical overload leads to cardiac hypertrophy and mechanical unloading to cardiac atrophy. Both conditions produce similar transcriptional changes including a re-expression of fetal genes, despite obvious differences in phenotype. MicroRNAs (miRNAs) are discussed as superordinate regulators of global gene networks acting mainly at the translational level. Here, we hypothesized that defined sets of miRNAs may determine the direction of cardiomyocyte plasticity responses. METHODOLOGY/PRINCIPAL FINDINGS: We employed ascending aortic stenosis (AS) and heterotopic heart transplantation (HTX) in syngenic Lewis rats to induce mechanical overloading and unloading, respectively. Heart weight was 26±3% higher in AS (n = 7) and 33±2% lower in HTX (n = 7) as compared to sham-operated (n = 6) and healthy controls (n = 7). Small RNAs were enriched from the left ventricles and subjected to quantitative stem-loop specific RT-PCR targeting a panel of 351 miRNAs. In total, 153 miRNAs could be unambiguously detected. Out of 72 miRNAs previously implicated in the cardiovascular system, 40 miRNAs were regulated in AS and/or HTX. Overall, HTX displayed a slightly broader activation pattern for moderately regulated miRNAs. Surprisingly, however, the regulation of individual miRNA expression was strikingly similar in direction and amplitude in AS and HTX with no miRNA being regulated in opposite direction. In contrast, fetal hearts from Lewis rats at embryonic day 18 exhibited an entirely different miRNA expression pattern. CONCLUSIONS: Taken together, our findings demonstrate that opposite changes in cardiac workload induce a common miRNA expression pattern which is markedly different from the fetal miRNA expression pattern. The direction of postnatal adaptive cardiac growth does, therefore, not appear to be determined at the level of single miRNAs or a specific set of miRNAs. Moreover, miRNAs themselves are not reprogrammed to a fetal program in response to changes in hemodynamic load

Neurovascular unit dysfunction with blood-brain barrier hyperpermeability contributes to major depressive disorder: a review of clinical and experimental evidence

About one-third of people with major depressive disorder (MDD) fail at least two antidepressant drug trials at 1 year. Together with clinical and experimental evidence indicating that the pathophysiology of MDD is multifactorial, this observation underscores the importance of elucidating mechanisms beyond monoaminergic dysregulation that can contribute to the genesis and persistence of MDD. Oxidative stress and neuroinflammation are mechanistically linked to the presence of neurovascular dysfunction with blood-brain barrier (BBB) hyperpermeability in selected neurological disorders, such as stroke, epilepsy, multiple sclerosis, traumatic brain injury, and Alzheimer’s disease. In contrast to other major psychiatric disorders, MDD is frequently comorbid with such neurological disorders and constitutes an independent risk factor for morbidity and mortality in disorders characterized by vascular endothelial dysfunction (cardiovascular disease and diabetes mellitus). Oxidative stress and neuroinflammation are implicated in the neurobiology of MDD. More recent evidence links neurovascular dysfunction with BBB hyperpermeability to MDD without neurological comorbidity. We review this emerging literature and present a theoretical integration between these abnormalities to those involving oxidative stress and neuroinflammation in MDD. We discuss our hypothesis that alterations in endothelial nitric oxide levels and endothelial nitric oxide synthase uncoupling are central mechanistic links in this regard. Understanding the contribution of neurovascular dysfunction with BBB hyperpermeability to the pathophysiology of MDD may help to identify novel therapeutic and preventative approaches