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• W2000634246 abstract "Background: Apoptosis Signal-regulating Kinase 1 (ASK1) is an upstream mitogen-activated protein kinase (also known as MAP3K5). ASK1 is activated in cells under oxidative stress (ROS), endoplasmatic reticulum (ER) stress, or after stimulation by lipopolysaccharide (LPS), cytokines, Fas ligand, GPCR agonists and calcium overload. Recent studies show that ASK1 serves as a mediator of cytokine and reactive oxygen species (ROS) signaling during the development of cardiomyocyte hypertrophy. Studies in mice revealed that ASK1 knock out results in reduced hypertrophy and fibrosis following pressure overload or myocardial infarction. Recognizing that proteins that interact with ASK1 could represent mechanisms through which ASK1 mediates cardiac pathology, we employed the yeast 2-hybrid method to identify proteins that interact with ASK1 in the failing human heart. Methods and Results: Through a yeast two-hybrid screen of a cDNA library made from tissue of a failing human heart, we discovered that ASK1 interacts with NPPA, the precursor of Atrial natriuretic peptide (ANP). ANP is an endogenous peptide hormone synthesized and secreted by the myocardium. Using an in vitro kinase assay, we demonstrated that NPPA is a substrate of ASK1. When expressed in Hela cells, ASK1 exhibits a diffuse cytoplasmic distribution with increased staining in the endoplasmic reticulum (ER) region and NPPA was mainly localized to the Golgi apparatus with weak staining in the ER region. The common ER staining by both proteins suggests a potential location for their interaction. Co-expression of ASK1 and NPPA in Hela cells led to reduced levels (50% less) of NPPA in the culture medium compared with expression of NPPA alone indicating that ASK1 functions as a negative regulator of NPPA secretion. When a dominant-negative allele of ASK1 that reported to lack the kinase activity was co-expressed in Hela cells with NPPA, the secretion of NPPA was reduced by about 35%. Conclusion: We conclude that the kinase activity of ASK1 could negatively regulate the secretion and processing of NPPA. Because recent studies indicate that ANP has anti-apoptotic and cardioprotective actions in failing and hypertrophied hearts, antagonism of ANP synthesis by ASK1 may contribute to pathological cardiac remodeling in states where ASK1 is activated, such as pressure overload and myocardial infarction. Background: Apoptosis Signal-regulating Kinase 1 (ASK1) is an upstream mitogen-activated protein kinase (also known as MAP3K5). ASK1 is activated in cells under oxidative stress (ROS), endoplasmatic reticulum (ER) stress, or after stimulation by lipopolysaccharide (LPS), cytokines, Fas ligand, GPCR agonists and calcium overload. Recent studies show that ASK1 serves as a mediator of cytokine and reactive oxygen species (ROS) signaling during the development of cardiomyocyte hypertrophy. Studies in mice revealed that ASK1 knock out results in reduced hypertrophy and fibrosis following pressure overload or myocardial infarction. Recognizing that proteins that interact with ASK1 could represent mechanisms through which ASK1 mediates cardiac pathology, we employed the yeast 2-hybrid method to identify proteins that interact with ASK1 in the failing human heart. Methods and Results: Through a yeast two-hybrid screen of a cDNA library made from tissue of a failing human heart, we discovered that ASK1 interacts with NPPA, the precursor of Atrial natriuretic peptide (ANP). ANP is an endogenous peptide hormone synthesized and secreted by the myocardium. Using an in vitro kinase assay, we demonstrated that NPPA is a substrate of ASK1. When expressed in Hela cells, ASK1 exhibits a diffuse cytoplasmic distribution with increased staining in the endoplasmic reticulum (ER) region and NPPA was mainly localized to the Golgi apparatus with weak staining in the ER region. The common ER staining by both proteins suggests a potential location for their interaction. Co-expression of ASK1 and NPPA in Hela cells led to reduced levels (50% less) of NPPA in the culture medium compared with expression of NPPA alone indicating that ASK1 functions as a negative regulator of NPPA secretion. When a dominant-negative allele of ASK1 that reported to lack the kinase activity was co-expressed in Hela cells with NPPA, the secretion of NPPA was reduced by about 35%. Conclusion: We conclude that the kinase activity of ASK1 could negatively regulate the secretion and processing of NPPA. Because recent studies indicate that ANP has anti-apoptotic and cardioprotective actions in failing and hypertrophied hearts, antagonism of ANP synthesis by ASK1 may contribute to pathological cardiac remodeling in states where ASK1 is activated, such as pressure overload and myocardial infarction." @default.
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• W2000634246 date "2008-08-01" @default.
• W2000634246 modified "2023-09-23" @default.
• W2000634246 title "Apoptosis Signal-Regulating Kinase 1 Attenuates Atrial Natriuretic Peptide Secretion" @default.
• W2000634246 doi "https://doi.org/10.1016/j.cardfail.2008.06.285" @default.
• W2000634246 hasPublicationYear "2008" @default.
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