Protective transcriptional mechanisms in cardiomyocytes and cardiac fibroblasts (original) (raw)
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Signaling pathways mediating cardiac myocyte gene expression in physiological and stress responses
Journal of Cellular Physiology, 2007
The contractile cells in the heart (the cardiac myocytes) are terminally differentiated. In response to pathophysiological stresses, cardiac myocytes undergo hypertrophic growth or apoptosis, responses associated with the development of cardiac pathologies. There has been much effort expended in gaining an understanding of the stimuli which promote these responses, and in identifying the intracellular signaling pathways which are activated and potentially involved. These signaling pathways presumably modulate gene and protein expression to elicit the end-stage response. For the regulation of gene expression, the signal may traverse the cytoplasm to modulate nuclear-localized transcription factors as occurs with the mitogen-activated protein kinase or protein kinase B/Akt cascades. Alternatively, the signal may promote translocation of transcription factors from the cytoplasm to the nucleus as is seen with the calcineurin/NFAT and JAK/STAT systems. We present an overview of the principal signaling pathways implicated in the regulation of gene expression in cardiac myocyte pathophysiology, and summarize the current understanding of these pathways, the transcription factors they regulate and the changes in gene expression associated with the development of cardiac pathologies. Finally, we discuss how intracellular signaling and gene expression may be integrated to elicit the overall change in cellular phenotype. J. Cell. Physiol. 212: 311–322, 2007. © 2007 Wiley-Liss, Inc.
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 ...
Cell, 1999
of the immune system, hepatic function, bone metabolism, neurological function, and hematopoiesis (Stewart et al.; Romano et al., 1997). Embryos that harbor ‡ Center for Molecular Genetics a complete deficiency in the common cytokine signal School of Medicine transducer gp130 display embryonic lethality and de-University of California, San Diego fects in diverse embryonic compartments (Yoshida et La Jolla, California 92093 al., 1996). Similarly, mice that lack the LIF receptor § Institute for Genetics (LIFR), the shared component of the receptor complexes University of Cologne for LIF, cardiotrophin-1 (CT-1), and CNTF, die in the Weyertal 121 perinatal window of development and exhibit placental, D-50931 Cologne skeletal, neural, and metabolic defects (Li et al., 1995; Germany Ware et al. , 1995). Unfortunately, given the pleiotropic effects of the IL-6 family on multiple tissues, and the genetic ablation of these widely expressed components Summary of the cytokine signaling pathway in virtually every cell type, it is often difficult to conclude from these studies Biomechanical stress is a major stimulus for cardiac whether these defects arise as a result of a primary or hypertrophy and the transition to heart failure. By secondary requirement for a specific cytokine signaling generating mice that harbor a ventricular restricted pathway. knockout of the gp130 cytokine receptor via Cre-loxP-Recently, this point has become of particular impormediated recombination, we demonstrate a critical tance in elucidating the specific role of the IL-6-related role for a gp130-dependent myocyte survival pathway cytokines in the pathogenesis of cardiac failure, the leadin the transition to heart failure. Such conditional muing cause of combined morbidity and mortality in the U.S. tant mice have normal cardiac structure and function, and other developed nations. In response to chronic but during aortic pressure overload, these mice disincreases in hemodynamic pressure (e.g., long-standing play rapid onset of dilated cardiomyopathy and mashypertension) and volume overload (e.g., postmyocarsive induction of myocyte apoptosis versus the control dial injury), the heart initiates an adaptive response of mice that exhibit compensatory hypertrophy. Thus, compensatory hypertrophy that leads to cardiac encardiac myocyte apoptosis is a critical point in the largement and a maintenance of normal cardiac functransition between compensatory cardiac hypertrotion. However, there can be a temporal transition under phy and heart failure. gp130-dependent cytokines may conditions of chronic stimulation where these biomerepresent a novel therapeutic strategy for preventing chanical stimuli subsequently activate pathways that in vivo heart failure.
Molecular Pharmacology, 2014
Activating transcription factor 3 (ATF3), a CREB/ATF family transcription factors member, has been implicated in cardiovascular and inflammatory system and is rapidly induced by ischemic-reperfusion injuries. We performed transverse aortic banding (TAB) experiments using ATF3 gene-deleted mice (ATF3-/-) and wild-type (WT) mice to find out what effect it may have on heart failure induced by pressure overloading. Compared to the WT mice, ATF3-/mice were found by echocardiography to have decreased left ventricular contractility with loss of normal cardiac hypertrophic remodeling. The ATF3-/mice had greater numbers of TUNEL-positive cells and higher levels of activated caspase-3 as well as more apoptosis. Restoration of ATF3 expression in the heart of ATF3-/mice by adenovirus-induced ATF3 treatment significantly improved cardiac contractility following TAB. The results from molecular and biochemical analyses, including chromatin immune-precipitation (ChIP) and in vitro /in vivo promoter assays, showed that ATF3 bound to the ATF/CRE element of the beclin-1 promoter and that ATF3 reduced autophagy via suppression of the beclin-1 dependent pathway. Furthermore, infusion of tert-butylhydroquinone (tBHQ), a selective ATF3 inducer, increased the expression of ATF3 via the NRF2 transcriptional factor, inhibited TAB-induced cardiac dilatation, and increased left ventricular contractility, thereby rescuing heart This article has not been copyedited and formatted. The final version may differ from this version.
Circulation. Heart failure, 2012
Numerous molecular and biochemical changes have been linked with the cardioprotective effects of exercise, including increases in antioxidant enzymes, heat shock proteins, and regulators of cardiac myocyte proliferation. However, a master regulator of exercise-induced protection has yet to be identified. Here, we assess whether phosphoinositide 3-kinase (PI3K) p110α is essential for mediating exercise-induced cardioprotection, and if so, whether its activation independent of exercise can restore function of the failing heart. Cardiac-specific transgenic (Tg) mice with elevated or reduced PI3K(p110α) activity (constitutively active PI3K [caPI3K] and dominant negative PI3K, respectively) and non-Tg controls were subjected to 4 weeks of exercise training followed by 1 week of pressure overload (aortic-banding) to induce pathological remodeling. Aortic-banding in untrained non-Tg controls led to pathological cardiac hypertrophy, depressed systolic function, and lung congestion. This phe...
The protective effects of exercise and phosphoinositide 3-kinase (p110α) in the failing heart
Clinical Science, 2009
Physical activity protects against cardiovascular disease, and physiological cardiac hypertrophy associated with regular exercise is usually beneficial, in marked contrast to pathological hypertrophy associated with disease. The p110␣ isoform of phosphoinositide 3-kinase (PI3K) plays a critical role in the induction of exerciseinduced hypertrophy. Whether it or other genes activated in the athlete's heart might have an impact on cardiac function and survival in a setting of heart failure is unknown. To examine whether progressive exercise training and PI3K(p110␣) activity affect survival and/or cardiac function in two models of heart disease, we subjected a transgenic mouse model of dilated cardiomyopathy (DCM) to swim training, genetically crossed cardiacspecific transgenic mice with increased or decreased PI3K(p110␣) activity to the DCM model, and subjected PI3K(p110␣) transgenics to acute pressure overload (ascending aortic constriction). Lifespan, cardiac function, and molecular markers of pathological hypertrophy were examined. Exercise training and increased cardiac PI3K(p110␣) activity prolonged survival in the DCM model by 15-20%. In contrast, reduced PI3K(p110␣) activity drastically shortened lifespan by Ϸ50%. Increased PI3K(p110␣) activity had a favorable effect on cardiac function and fibrosis in the pressureoverload model and attenuated pathological growth. PI3K(p110␣) signaling negatively regulated G protein-coupled receptor stimulated extracellular responsive kinase and Akt (via PI3K, p110␥) activation in isolated cardiomyocytes. These findings suggest that exercise and enhanced PI3K(p110␣) activity delay or prevent progression of heart disease, and that supraphysiologic activity can be beneficial. Identification of genes important for hypertrophy in the athlete's heart could offer new strategies for treating heart failure.