Signaling pathways mediating cardiac myocyte gene expression in physiological and stress responses (original) (raw)
Related papers
2003
During cardiac hypertrophy individual cardiac myocytes increase in size, which is accompanied by augmented protein synthesis and selective induction of a subset of genes. These phenotypic changes of myocytes are a result from altered intracellular signaling mechanisms and molecules. B-type natriuretic peptide (BNP) gene was selected as a target gene for the study of cardiac signaling mechanisms, since it is activated by mechanical, neural and humoral stimuli during myocyte hypertrophy. To generate hypertrophy of cardiac myocytes, neonatal rat cardiac myocytes were subjected to exogenous hypertrophic agonists such as endothelin-1 (ET-1) or to cyclic mechanical stretch. The role and regulation of transcription factors were studied by utilizing promoter analysis together with site-specific mutations and measurement of DNA binding activity and phosphorylation. GATA-4 mediated signaling was inhibited by blocking DNA binding with decoy oligonucleotides or by decreasing GATA-4 synthesis via adenoviral antisense delivery. ET-1 activated GATA-4 via serine residue phosphorylation, and this effect was mediated via p38 kinase. Similarly, GATA-4 binding activity was increased by ET-1 and mechanical stretch, but it was essential for activation of BNP gene only in the latter stimulation. Importantly, downregulation of GATA-4 protein levels prevented mechanical stretch induced hypertrophy of cardiac myocytes. In contrast, separate mechanism for an ET-1 specific signaling was composed of p38 kinase regulated ETS-like transcription factor-1 (Elk-1). Finally, the effect of mechanical stretch on endogenous endothelin-1 (ET-1) synthesis in cardiac cells was studied. Intrinsic ET-1 synthesis was activated in stretched cardiac myocytes, yet the levels of ET-1 were relatively low. This work suggests that GATA-4 transcription factor is required for mechanical stretch mediated hypertrophic program, and Elk-1 may act as a downstream effector of ET-1 in cardiac myocytes. Taken together, induction of ET-1 and BNP genes as well as activation of GATA-4 and Elk-1 transcription factors are regulated via a network of mitogen activated protein kinase pathways.
Stress signalling to cardiac gene expression and cell death
2018
Background: Cardiovascular diseases such as heart failure and myocardial infarction are associated with increased oxidative stress, the release of pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNFα) and interleukin 1β (IL1β) and increased death of the contractile cardiomyocytes. Oxidative stress (exemplified by H2O2) is a pivotal modulator of the balance between the life and death of cardiomyocytes. H2O2 promotes cardiomyocyte apoptosis, induces substantial changes in gene expression and activates the three principal mitogen-activated protein kinase (MAPK) pathways (ERK1/2, JNKs and p38-MAPKs), which regulate gene expression in other cell types. However, the roles of the MAPK pathways in regulation of cardiomyocyte gene expression in response to H2O2 are yet to be reported. A further pathway that may play important roles cardiac survival vs death is regulated by the protein kinase, RIPK1. In non-cardiac cell types, TNFα signals via RIPK1 to cytoprotection or cell ...
Protective transcriptional mechanisms in cardiomyocytes and cardiac fibroblasts
Journal of Molecular and Cellular Cardiology, 2019
Heart failure is the leading cause of morbidity and mortality worldwide. Several lines of evidence suggest that physical activity and exercise can precondition the heart to improve the response to acute cardiac injury such as myocardial infarction or ischemia/reperfusion injury, preventing the progression to heart failure. It is becoming more apparent that cardioprotection is a concerted effort between multiple cell types and converging signaling pathways. However, the molecular mechanisms of cardioprotection are not completely understood. What is clear is that the mechanisms underlying this protection involve acute activation of transcriptional activators and their corresponding gene expression programs. Here, we review the known stress-dependent transcriptional programs that are activated in cardiomyocytes and cardiac fibroblasts to preserve function in the adult heart after injury. Focus is given to prominent transcriptional pathways such as mechanical stress or reactive oxygen species (ROS)-dependent activation of myocardin-related transcription factors (MRTFs) and transforming growth factor beta (TGFβ), and gene expression that positively regulates protective PI3K/Akt signaling. Together, these pathways modulate both beneficial and pathological responses to cardiac injury in a cell-specific manner.
Molecular regulation of cardiac hypertrophy
International Journal of Biochemistry & Cell Biology, 2008
Heart failure is one of the leading causes of mortality in the western world and encompasses a wide spectrum of cardiac pathologies. When the heart experiences extended periods of elevated workload, it undergoes hypertrophic enlargement in response to the increased demand. Cardiovascular disease, such as that caused by myocardial infarction, obesity or drug abuse promotes cardiac myocyte hypertrophy and subsequent heart failure. A number of signalling modulators in the vasculature milieu are known to regulate heart mass including those that influence gene expression, apoptosis, cytokine release and growth factor signalling. Recent evidence using genetic and cellular models of cardiac hypertrophy suggests that pathological hypertrophy can be prevented or reversed and has promoted an enormous drive in drug discovery research aiming to identify novel and specific regulators of hypertrophy. In this review we describe the molecular characteristics of cardiac hypertrophy such as the aberrant re-expression of the fetal gene program. We discuss the various molecular pathways responsible for the co-ordinated control of the hypertrophic program including: natriuretic peptides, the adrenergic system, adhesion and cytoskeletal proteins, IL-6 cytokine family, MEK-ERK1/2 signalling, histone acetylation, calcium-mediated modulation and the exciting recent discovery of the role of microRNAs in controlling cardiac hypertrophy. Characterisation of the signalling pathways leading to cardiac hypertrophy has led to a wealth of knowledge about this condition both physiological and pathological. The challenge will be translating this knowledge into potential pharmacological therapies for the treatment of cardiac pathologies.
British Journal of Pharmacology, 2010
Background and purpose: The mixed-lineage kinases (MLKs) act upstream of mitogen-activated protein kinases, but their role in cardiac biology and pathology is largely unknown. Experimental approach: We investigated the effect of a MLK1-3 inhibitor CEP-11004 on G protein-coupled receptor agonist-induced stress response in neonatal rat cardiac myocytes in culture. Key results: CEP-11004 administration dose-dependently attenuated phenylephrine and endothelin-1 (ET-1)-induced c-Jun N-terminal kinase activation. MLK inhibition also reduced ET-1-and phenylephrine-induced phosphorylation of p38 mitogenactivated protein kinase. In contrast, phenylephrine-induced extracellular signal-regulated kinase phosphorylation was further up-regulated by CEP-11004. ET-1 increased activator protein-1 binding activity 3.5-fold and GATA-binding protein 4 (GATA-4) binding activity 1.8-fold, both of which were attenuated with CEP-11004 administration by 59% and 63% respectively. Phenylephrine induced activator protein-1 binding activity by 2.6-fold, which was decreased by 81% with CEP-11004 administration. Phenylephrine also induced a 3.7-fold increase in the transcriptional activity of B-type natriuretic peptide (BNP), which was attenuated by 41% with CEP-11004 administration. In agreement, MLK inhibition also reduced hypertrophic agonist-induced secretion of immunoreactive atrial natriuretic peptide and BNP. Conclusions and implications: These results showed that inhibition of the MLK1-3 signalling pathway was sufficient for suppressing the activity of key nuclear effectors (GATA-4 and activator protein-1 transcription factors) in cardiac hypertrophy, and attenuated the agonist-induced atrial natriuretic peptide secretion and activation of BNP gene transcription.
Re-expression of proteins involved in cytokinesis during cardiac hypertrophy
Experimental Cell Research, 2007
Cardiomyocytes stop dividing after birth and postnatal heart growth is only achieved by increase in cell volume. In some species, cardiomyocytes undergo an additional incomplete mitosis in the first postnatal week, where karyokinesis takes place in the absence of cytokinesis, leading to binucleation. Proteins that regulate the formation of the actomyosin ring are known to be important for cytokinesis. Here we demonstrate for the first time that small GTPases like RhoA along with their downstream effectors like ROCK I, ROCK II and Citron Kinase show a developmental stage specific expression in heart, with high levels being expressed in cardiomyocytes only at stages when cytokinesis still occurs (i.e. embryonic and perinatal). This suggests that downregulation of many regulatory and cytoskeletal components involved in the formation of the actomyosin ring may be responsible for the uncoupling of cytokinesis from karyokinesis in rodent cardiomyocytes after birth. Interestingly, when the myocardium tries to adapt to the increased workload during pathological hypertrophy a re-expression of proteins involved in DNA synthesis and cytokinesis can be detected. Nevertheless, the adult cardiomyocytes do not appear to divide despite this upregulation of the cytokinetic machinery. The inability to undergo complete division could be due to the presence of stable, highly ordered and functional sarcomeres in the adult myocardium or could be because of the inefficiency of degradation pathways, which facilitate the division of differentiated embryonic cardiomyocytes by disintegrating myofibrils.
Nuclear Ca2+/calmodulin-dependent protein kinase II in the murine heart
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2006
Ca(2+) signaling through CaMKII is critical in regulating myocyte function with regard to excitation-contraction-relaxation cycles and excitation-transcription coupling. To investigate the role of nuclear CaMKII in cardiac function, transgenic mice were designed and generated to target the expression of a CaMKII inhibitory peptide, AIP (KKALRRQEAVDAL), to the nucleus. The transgenic construct consists of the murine alpha-myosin heavy chain promoter followed by the expression unit containing nucleotides encoding a four repeat concatemer of AIP (AIP(4)) and a nuclear localization signal (NLS). Western blot and immunohistochemical analyses demonstrate that AIP(4) is expressed only in the nucleus of cardiac myocytes of the transgenic mice (NLS-AIP(4)). The function of cytoplasmic CaMKII is not affected by the expression of AIP(4) in the nucleus. Inhibition of nuclear CaMKII activity resulted in reduced translocation of HDAC5 from nucleus to cytoplasm in NLS-AIP(4) mouse hearts. Loss of nuclear CaMKII activity causes NLS-AIP(4) mice to have smaller hearts than their nontransgenic littermates. Transcription factors including CREB and NFkappaB are not regulated by cardiac nuclear CaMKII. With physiological stresses such as pregnancy or aging (8 months), NLS-AIP(4) mice develop hypertrophy symptoms including enlarged atria, systemic edema, sedentariness, and morbidity. RT-PCR analyses revealed that the hypertrophic marker genes, such as ANF and beta-myosin heavy chain, were upregulated in pregnancy stressed mice. Our results suggest that absence of adequate Ca2+signaling through nuclear CaMKII regulated pathways leads to development of cardiac disease.