Abstract
AimsActivating transcription factor 3 (ATF3) is a stress-activated immediate early gene suggested to have both detrimental and cardioprotective role in the heart. Here we studied the mechanisms of ATF3 activation by hypertrophic stimuli and ATF3 downstream targets in rat cardiomyocytes.Methods and ResultsWhen neonatal rat cardiomyocytes were exposed to endothelin-1 (ET-1, 100 nM) and mechanical stretching in vitro, maximal increase in ATF3 expression occurred at 1 hour. Inhibition of extracellular signal-regulated kinase (ERK) by PD98059 decreased ET-1– and stretch–induced increase of ATF3 protein but not ATF3 mRNA levels, whereas protein kinase A (PKA) inhibitor H89 attenuated both ATF3 mRNA transcription and protein expression in response to ET-1 and stretch. To characterize further the regulatory mechanisms upstream of ATF3, p38 mitogen-activated protein kinase (MAPK) signaling was investigated using a gain-of-function approach. Adenoviral overexpression of p38α, but not p38β, increased ATF3 mRNA and protein levels as well as DNA binding activity. To investigate the role of ATF3 in hypertrophic process, we overexpressed ATF3 by adenovirus-mediated gene transfer. In vitro, ATF3 gene delivery attenuated the mRNA transcription of interleukin-6 (IL-6) and plasminogen activator inhibitor-1 (PAI-1), and enhanced nuclear factor-κB (NF-κB) and Nkx-2.5 DNA binding activities. Reduced PAI-1 expression was also detected in vivo in adult rat heart by direct intramyocardial adenovirus-mediated ATF3 gene delivery.ConclusionsThese data demonstrate that ATF3 activation by ET-1 and mechanical stretch is partly mediated through ERK and cAMP-PKA pathways, whereas p38 MAPK pathway is involved in ATF3 activation exclusively through p38α isoform. ATF3 activation caused induction of modulators of the inflammatory response NF-κB and Nkx-2.5, as well as attenuation of pro-fibrotic and pro-inflammatory proteins IL-6 and PAI-1, suggesting cardioprotective role for ATF3 in the heart.
Highlights
Most patients with heart failure have a history of left ventricular hypertrophy, which is initially an adaptive response to increased work load
These data demonstrate that Activating transcription factor 3 (ATF3) activation by ET-1 and mechanical stretch is partly mediated through extracellular signal-regulated kinase (ERK) and cAMP-protein kinase A (PKA) pathways, whereas p38 mitogen-activated protein kinase (MAPK) pathway is involved in ATF3 activation exclusively through p38a isoform
In the present study we demonstrate that ERK and PKA pathways are involved in ATF3 activation in response to ET-1 stimulation and mechanical stretching of neonatal rat cardiomyocytes (NRCM), and that the main p38 MAPK isoform upstream of ATF3 is p38a
Summary
Most patients with heart failure have a history of left ventricular hypertrophy, which is initially an adaptive response to increased work load. After sustained external load, hearts can evolve to a state of decompensated hypertrophy resulting in the dilatation of the left ventricle and loss of contractile function [1,2]. In response to hypertrophic stimuli, a fundamental reprogramming occurs within the adult cardiomyocytes that results in the expression of genes encoding fetal protein isoforms. The immediate early genetic response includes transcription of genes such as c-fos, c-jun and early growth response–1 (EGR-1). Later during the hypertrophic process, the transcription of contractile proteins, a-myosin heavy chain (a-MHC) and cardiac a-actin, are downregulated and expression of b-MHC and skeletal muscle a-actin are up-regulated. Non-contractile proteingenes such as atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) become highly expressed within ventricular myocytes [3]
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