Biomedical subjects

Eric N Olson

Publications and source records attributed to Eric N Olson.

At least 91 records · Page 5Linked to original sources

PubMed2004

A small molecular activator of cardiac hypertrophy uncovered in a chemical screen for modifiers of the calcineurin signaling pathway.

The calcium, calmodulin-dependent phosphatase calcineurin, regulates growth and gene expression of striated muscles. The activity of calcineurin is modulated by a family of cofactors, referred to as modulatory calcineurin-interacting proteins (MCIPs). In the heart, the MCIP1 gene is activated by calcineurin and has been proposed to fulfill a negative feedback loop that restrains potentially pathological calcineurin signaling, which would otherwise lead to abnormal cardiac growth. In a high-throughput screen for small molecules capable of regulating MCIP1 expression in muscle cells, we identified a unique 4-aminopyridine derivative exhibiting an embedded partial structural motif of serotonin (5-hydroxytryptamine, 5-HT). This molecule, referred to as pyridine activator of myocyte hypertrophy, acts as a selective agonist for 5-HT(2A/2B) receptors and induces hypertrophy of cardiac muscle cells through a signaling pathway involving calcineurin and a kinase-dependent mechanism that inactivates class II histone deacetylases, which act as repressors of cardiac growth. These findings identify MCIP1 as a downstream target of 5-HT(2A/2B) receptor signaling in cardiac muscle cells and suggest possible uses for 5-HT(2A/2B) agonists and antagonists as modulators of cardiac growth and gene expression.

Animals↗

PubMed2004

MCIP1 overexpression suppresses left ventricular remodeling and sustains cardiac function after myocardial infarction.

Pathological remodeling of the left ventricle (LV) after myocardial infarction (MI) is a major cause of heart failure. Although cardiac hypertrophy after increased loading conditions has been recognized as a clinical risk factor for human heart failure, it is unknown whether post-MI hypertrophic remodeling of the myocardium is beneficial for cardiac function over time, nor which regulatory pathways play a crucial role in this process. To address these questions, transgenic (TG) mice engineered to overexpress modulatory calcineurin-interacting protein-1 (MCIP1) in the myocardium were used to achieve cardiac-specific inhibition of calcineurin activation. MCIP1-TG mice and their wild-type (WT) littermates, were subjected to MI and analyzed 4 weeks later. At 4 weeks after MI, calcineurin was activated in the LV of WT mice, which was significantly reduced in MCIP1-TG mice. WT mice displayed a 78% increase in LV mass after MI, which was reduced by 38% in MCIP1-TG mice. Echocardiography indicated marked LV dilation and loss of systolic function in WT-MI mice, whereas TG-MI mice displayed a remarkable preservation of LV geometry and contractility, a pronounced reduction in myofiber hypertrophy, collagen deposition, and beta-MHC expression compared with WT-MI mice. Together, these results reveal a protective role for MCIP1 in the post-MI heart and suggest that calcineurin is a crucial regulator of postinfarction-induced pathological LV remodeling. The improvement in functional, structural, and molecular abnormalities in MCIP1-TG mice challenges the adaptive value of post-MI hypertrophy of the remote myocardium. The full text of this article is available online at http://circres.ahajournals.org.

Animals↗

PubMed2004

Control of smooth muscle development by the myocardin family of transcriptional coactivators.

Differentiation of smooth muscle cells (SMCs) is accompanied by the transcriptional activation of an array of muscle-specific genes that confer the unique contractile and physiologic properties of this muscle cell type. The majority of smooth muscle genes are controlled by serum response factor (SRF), a widely expressed transcription factor that also regulates genes involved in cell proliferation. Myocardin and myocardin-related transcription factors (MRTFs) interact with SRF and potently stimulate SRF-dependent transcription. Gain- and loss-of-function experiments have shown myocardin to be sufficient and necessary for SMC differentiation. SMCs are highly plastic and can switch between differentiated and proliferative states in response to extracellular cues. Suppression of SMC differentiation by growth factor signaling is mediated, at least in part, by the displacement of myocardin from SRF by growth factor-dependent ternary complex factors. The association of SRF with myocardin and MRTFs provides a molecular basis for the activation of SMC genes by SRF and the responsiveness of the smooth muscle differentiation program to growth factor signaling.

Animals↗

PubMed2004

Towards a molecular pathway for myoblast fusion in Drosophila.

Intercellular fusion among myoblasts is required for the generation of multinucleated muscle fibers during skeletal muscle development. Recent studies in Drosophila have shed light on the molecular mechanisms that underlie this process, and a signaling pathway that relays fusion signals from the cell membrane to the cytoskeleton has emerged. In this article, we review these recent advances and discuss how Drosophila offers a powerful model system to study myoblast fusion in vivo.

Animals↗

PubMed2004

Cardiac histone acetylation--therapeutic opportunities abound.

Diverse etiologic factors trigger a cardiac remodeling process in which the heart becomes abnormally enlarged with a consequent decline in cardiac function and eventual heart failure. Heart failure is traditionally treated with drugs that antagonize early signaling events at or near the cell membrane. Although such approaches have short-term efficacy, the five-year mortality rate for patients with late-stage heart failure continues to exceed 50%. Because of the redundant nature of the signaling networks that drive cardiac pathogenesis, targeting the common downstream elements of the cascades would be a more effective therapeutic strategy. Recent studies point to the importance of enzymes that control histone acetylation as stress-responsive regulators of gene expression in the heart. Given their role as nuclear integrators that couple divergent upstream signals to the gene program for cardiac remodeling, we propose that these chromatin-modifying factors represent auspicious targets for the pharmacological manipulation of cardiac disease.

Acetylation↗

PubMed2004

A twist code determines the onset of osteoblast differentiation.

Runx2 is necessary and sufficient for osteoblast differentiation, yet its expression precedes the appearance of osteoblasts by 4 days. Here we show that Twist proteins transiently inhibit Runx2 function during skeletogenesis. Twist-1 and -2 are expressed in Runx2-expressing cells throughout the skeleton early during development, and osteoblast-specific gene expression occurs only after their expression decreases. Double heterozygotes for Twist-1 and Runx2 deletion have none of the skull abnormalities observed in Runx2(+/-) mice, a Twist-2 null background rescues the clavicle phenotype of Runx2(+/-) mice, and Twist-1 or -2 deficiency leads to premature osteoblast differentiation. Furthermore, Twist-1 overexpression inhibits osteoblast differentiation without affecting Runx2 expression. Twist proteins' antiosteogenic function is mediated by a novel domain, the Twist box, which interacts with the Runx2 DNA binding domain to inhibit its function. In vivo mutagenesis confirms the antiosteogenic function of the Twist box. Thus, relief of inhibition by Twist proteins is a mandatory event precluding osteoblast differentiation.

Aging↗

PubMed2004

A decade of discoveries in cardiac biology.

The heart is the first organ to form in the embryo, and all subsequent events in the life of the organism depend on its function. Inherited mutations in cardiac regulatory genes give rise to congenital heart disease, the most common form of human birth defects, and abnormalities of the adult heart represent the most prevalent cause of morbidity and mortality in the industrialized world. The past decade has marked a transition from physiological and functional studies of the heart toward a deeper understanding of cardiac function (and dysfunction) at genetic and molecular levels. These discoveries have provided new therapeutic approaches for prevention and palliation of cardiac disease and have raised new questions, challenges and opportunities for the future.

Animals↗

PubMed2004

Protein kinases C and D mediate agonist-dependent cardiac hypertrophy through nuclear export of histone deacetylase 5.

A variety of stress signals stimulate cardiac myocytes to undergo hypertrophy. Persistent cardiac hypertrophy is associated with elevated risk for the development of heart failure. Recently, we showed that class II histone deacetylases (HDACs) suppress cardiac hypertrophy and that stress signals neutralize this repressive function by triggering phosphorylation- and CRM1-dependent nuclear export of these chromatin-modifying enzymes. However, the identities of cardiac HDAC kinases have remained unclear. Here, we demonstrate that signaling by protein kinase C (PKC) is sufficient and, in some cases, necessary to drive nuclear export of class II HDAC5 in cardiomyocytes. Inhibition of PKC prevents nucleocytoplasmic shuttling of HDAC5 in response to a subset of hypertrophic agonists. Moreover, a nonphosphorylatable HDAC5 mutant is refractory to PKC signaling and blocks cardiomyocyte hypertrophy mediated by pharmacological activators of PKC. We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. These findings reveal a novel function for the PKC/PKD axis in coupling extracellular cues to chromatin modifications that control cellular growth, and they suggest potential utility for small-molecule inhibitors of this pathway in the treatment of pathological cardiac gene expression.

Animals↗

PubMed2004

Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development.

The adult heart responds to stress signals by hypertrophic growth, which is often accompanied by activation of a fetal cardiac gene program and eventual cardiac demise. We showed previously that histone deacetylase 9 (HDAC9) acts as a suppressor of cardiac hypertrophy and that mice lacking HDAC9 are sensitized to cardiac stress signals. Here we report that mice lacking HDAC5 display a similar cardiac phenotype and develop profoundly enlarged hearts in response to pressure overload resulting from aortic constriction or constitutive cardiac activation of calcineurin, a transducer of cardiac stress signals. In contrast, mice lacking either HDAC5 or HDAC9 show a hypertrophic response to chronic beta-adrenergic stimulation identical to that of wild-type littermates, suggesting that these HDACs modulate a specific subset of cardiac stress response pathways. We also show that compound mutant mice lacking both HDAC5 and HDAC9 show a propensity for lethal ventricular septal defects and thin-walled myocardium. These findings reveal central roles for HDACs 5 and 9 in the suppression of a subset of cardiac stress signals as well as redundant functions in the control of cardiac development.

Animals↗

PubMed2004

Target gene-specific modulation of myocardin activity by GATA transcription factors.

Myocardin is a transcriptional coactivator that regulates cardiac and smooth muscle gene expression by associating with serum response factor. We show that GATA transcription factors can either stimulate or suppress the transcriptional activity of myocardin, depending on the target gene. Modulation of myocardin activity by GATA4 is mediated by the physical interaction of myocardin with the DNA binding domain of GATA4 but does not require binding of GATA4 to DNA. Paradoxically, the transcription activation domain of GATA4 is dispensable for the stimulatory effect of GATA4 on myocardin activity but is required for repression of myocardin activity. The ability of GATA transcription factors to modulate myocardin activity provides a potential mechanism for fine tuning the expression of serum response factor target genes in a gene-specific manner.

Animals↗

PubMed2004

HRC is a direct transcriptional target of MEF2 during cardiac, skeletal, and arterial smooth muscle development in vivo.

The HRC gene encodes the histidine-rich calcium-binding protein, which is found in the lumen of the junctional sarcoplasmic reticulum (SR) of cardiac and skeletal muscle and within calciosomes of arterial smooth muscle. The expression of HRC in cardiac, skeletal, and smooth muscle raises the possibility of a common transcriptional mechanism governing its expression in all three muscle cell types. In this study, we identified a transcriptional enhancer from the HRC gene that is sufficient to direct the expression of lacZ in the expression pattern of endogenous HRC in transgenic mice. The HRC enhancer contains a small, highly conserved sequence that is required for expression in all three muscle lineages. Within this conserved region is a consensus site for myocyte enhancer factor 2 (MEF2) proteins that we show is bound efficiently by MEF2 and is required for transgene expression in all three muscle lineages in vivo. Furthermore, the entire HRC enhancer sequence lacks any discernible CArG motifs, the binding site for serum response factor (SRF), and we show that the enhancer is not activated by SRF. Thus, these studies identify the HRC enhancer as the first MEF2-dependent, CArG-independent transcriptional target in smooth muscle and represent the first analysis of the transcriptional regulation of an SR gene in vivo.

Amino Acid Motifs↗

PubMed2004

Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore.

Environmental stresses converge on the mitochondria that can trigger or inhibit cell death. Excitable, postmitotic cells, in response to sublethal noxious stress, engage mechanisms that afford protection from subsequent insults. We show that reoxygenation after prolonged hypoxia reduces the reactive oxygen species (ROS) threshold for the mitochondrial permeability transition (MPT) in cardiomyocytes and that cell survival is steeply negatively correlated with the fraction of depolarized mitochondria. Cell protection that exhibits a memory (preconditioning) results from triggered mitochondrial swelling that causes enhanced substrate oxidation and ROS production, leading to redox activation of PKC, which inhibits glycogen synthase kinase-3beta (GSK-3beta). Alternatively, receptor tyrosine kinase or certain G protein-coupled receptor activation elicits cell protection (without mitochondrial swelling or durable memory) by inhibiting GSK-3beta, via protein kinase B/Akt and mTOR/p70(s6k) pathways, PKC pathways, or protein kinase A pathways. The convergence of these pathways via inhibition of GSK-3beta on the end effector, the permeability transition pore complex, to limit MPT induction is the general mechanism of cardiomyocyte protection.

Animals↗

PubMed2004

Undermining the endothelium by ablation of MAPK-MEF2 signaling.

Numerous stimuli activate Big MAPK-1 (BMK1), an MAPK that activates the myocyte enhancer factor-2 (MEF2) transcription factor. Conditional gene deletion showed BMK1 to be required for survival of endothelial cells. An active form of MEF2C could partially bypass the requirement for BMK1 for endothelial cell survival in vitro. These findings reveal an essential role for BMK1-MEF2 signaling in an endothelial cell survival pathway and raise interesting questions about the molecular basis of this response.

Animals↗

PubMed2004

Balancing contractility and energy production: the role of myocyte enhancer factor 2 (MEF2) in cardiac hypertrophy.

Cardiac hypertrophy -- that is, enlargement of the heart resulting from increased myocyte size -- is observed with many forms of human heart disease. It may arise secondary to an insult, such as infarct or chronic hypertension, or may occur as a consequence of a genetic defect, such as in hypertrophic cardiomyopathy. Traditionally, it has been widely believed that hypertrophy occurred as an adaptive response to normalize increased wall stress due to disease. Recently, however, it has been observed that while hypertrophy initially appears to improve the function of the heart following insult, over time, it frequently leads to a decompensated state, characterized by fibrosis and chamber dilation, resulting in overt heart failure. Hypertrophy also occurs during fetal development, immediately after birth, and in trained athletes; however, it does not lead to decompensation in these states. Experiments over the last 15 years have implicated similar signaling pathways in both pathological and physiological hypertrophic responses. Recently, important differences have been demonstrated that might hold the key to the development of effective new treatments for human diseases. This chapter focuses on how these hypertrophic responses differ from one another phenotypically and discusses how inefficient or impaired energy metabolism in the heart may contribute to the development of pathological responses. We also discuss recent evidence that the myocyte enhancer factor 2 (MEF2) transcription factor family, which previously has been shown to be important in cardiac development and hypertrophy, may have a role in regulation of cardiac energy metabolism.

Animals↗

PubMed2004

Dual roles of histone deacetylases in the control of cardiac growth.

Diverse aetiological factors, including myocardial infarction, hypertension and contractile abnormalities, trigger a cardiac remodelling process in which the heart becomes abnormally enlarged with a consequent decline in cardiac function and eventual heart failure. Pathological cardiac hypertrophy is accompanied by the activation of a fetal cardiac gene programme, which contributes to maladaptive changes in contractility and calcium handling. Traditional treatment for heart failure involves administration of drugs that antagonize early signalling events at or near the cell membrane (e.g. cell surface receptor or ion channels). Given the complexity and redundant nature of the signalling networks that drive cardiac pathogenesis, a potentially more efficacious therapeutic strategy for disrupting the disease process would be to target common downstream elements in pathological signalling cascades. We have shown that class II histone deacetylases (HDACs) suppress cardiac hypertrophy, and mice lacking class II HDACs are sensitized to hypertrophic signals. Paradoxically, HDAC inhibitors also block cardiac hypertrophy and fetal gene activation. Based on these findings, we propose that distinct HDACs play positive or negative roles in the control of cardiac growth by regulating opposing sets of target genes via their interactions with different sets of transcription factors.

Animals↗

PubMed2003

Nuclear factor-kappaB protects the adult cardiac myocyte against ischemia-induced apoptosis in a murine model of acute myocardial infarction.

BACKGROUND: Previous studies have shown that tumor necrosis factor (TNF) confers cytoprotective responses in cardiac myocytes. However, the mechanisms for the cytoprotective effects of TNF remain unknown. Given that TNF signals through nuclear factor kappaB (NF-kappaB) and given that NF-kappaB mediates cytoprotective responses, we asked whether NF-kappaB activation conferred cytoprotective responses in acute myocardial ischemia/infarction. METHODS AND RESULTS: We examined infarct size and the prevalence of apoptosis in transgenic mice harboring cardiac-restricted expression of a mutated IkappaBalpha protein (IkappaBalphaDeltaN) that prevents nuclear translocation of NF-kappaB in cardiac myocytes. Triphenyltetrazolium chloride staining showed that infarct size was approximately 50% greater (P<0.02) in the IkappaBalphaDeltaN mice compared with littermate controls at 24 hours. The prevalence of cardiac myocyte apoptosis was significantly greater (P<0.008) in the IkappaBalphaDeltaN mice compared with the littermate control mice 3 and 6 hours after left anterior descending occlusion. To explore the mechanism for these findings, we examined protein levels of c-IAP1, c-IAP2, and Bcl-2 as well as manganese superoxide dismutase and c-Jun NH2-terminal kinase activity. These studies showed that protein levels of c-IAP1 and Bcl-2 were significantly lower in the IkappaBalphaDeltaN mice, whereas there was no change in c-IAP2 levels, manganese superoxide dismutase, or c-Jun NH2-terminal kinase activity. CONCLUSIONS: Transgenic mice with a defect in activation of NF-kappaB have increased susceptibility to tissue injury after acute left anterior descending occlusion. These studies suggest that the cytoprotective effects of NF-kappaB are mediated, at least in part, by Bcl-2 or c-IAP1.

Animals↗

PubMed2003

Coronary artery disease and the MEF2A transcription factor.

Coronary artery disease (CAD) that results from lesions of the vascular wall is a major cause of myocardial infarction (MI) and stroke. A human pedigree with a predisposition to CAD and MI has been shown to harbor a mutation in the MEF2A transcription factor. These findings reveal a new function for this regulator of cardiovascular development and raise intriguing questions about the underlying mechanisms of CAD.

Coronary Artery Disease↗

PubMed2003

Role of calcineurin in striated muscle: development, adaptation, and disease.

Striated muscles, cardiac and skeletal muscles, use calcium as a second messenger to respond and adapt to environmental stimuli. Elevations in intracellular calcium activate calcineurin, a serine/threonine phosphatase, resulting in expression of a set of genes involved in remodeling striated muscle. Activation of calcineurin in hearts produces cardiac hypertrophy, and in skeletal muscle promotes cell differentiation and transforms fiber type specificity. In this review we discuss the effects of calcineurin activity on development, adaptation, and disease of striated muscle.

Adaptation, Physiological↗