Abstract
Angiotensin II inhibits insulin-induced activation of phosphatidylinositol 3-kinase through a mechanism, at least in part, dependent on serine phosphorylation of the insulin receptor and insulin receptor substrates (IRS)-1/2. Recent evidence shows that suppressor of cytokine signaling-3 (SOCS-3) is induced by insulin and angiotensin II and participates in the negative control of further stimulation of each of these signaling systems independently. In the present study, we evaluated the interaction of angiotensin II-induced SOCS-3 with the insulin signaling pathway in the heart of living rats. A single iv dose of angiotensin II promotes a significant increase of SOCS-3 in heart, an effect that lasts up to 180 min. Once induced, SOCS-3 interacts with the insulin receptor, JAK-2, IRS-1, and IRS-2. The inhibition of SOCS-3 expression by a phosphorthioate-modified antisense oligonucleotide partially restores angiotensin II-induced inhibition of insulin-induced insulin receptor, IRS-1 and IRS-2 tyrosine phosphorylation, and IRS-1 and IRS-2 association with p85-phosphatidylinositol 3-kinase and [Ser473] phosphorylation of Akt. Moreover, the inhibition of SOCS-3 expression partially reverses angiotensin II-induced inhibition of insulin-stimulated glucose transporter-4 translocation to the cell membrane. These results are reproduced in isolated cardiomyocytes. Thus, SOCS-3 participates, as a late event, in the negative cross-talk between angiotensin II and insulin, producing an inhibitory effect on insulin-induced glucose transporter-4 translocation.
MeSH terms
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Angiotensin II / metabolism*
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Animals
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DNA-Binding Proteins / metabolism
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Gene Expression
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Glucose Transporter Type 4
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Insulin / metabolism*
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Insulin Receptor Substrate Proteins
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Intracellular Signaling Peptides and Proteins
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Janus Kinase 2
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Male
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Milk Proteins / metabolism
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Monosaccharide Transport Proteins / metabolism
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Muscle Proteins / metabolism
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Myocytes, Cardiac / metabolism*
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Oligonucleotides, Antisense / pharmacology
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Phosphoproteins / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Rats
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Rats, Wistar
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Receptor Cross-Talk / physiology
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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STAT5 Transcription Factor
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Serine / metabolism
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Signal Transduction / physiology*
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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DNA-Binding Proteins
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Glucose Transporter Type 4
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Insulin
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Insulin Receptor Substrate Proteins
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Intracellular Signaling Peptides and Proteins
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Irs1 protein, rat
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Irs2 protein, rat
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Milk Proteins
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Monosaccharide Transport Proteins
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Muscle Proteins
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Oligonucleotides, Antisense
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Phosphoproteins
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Proto-Oncogene Proteins
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Repressor Proteins
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SOCS3 protein, human
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STAT5 Transcription Factor
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Slc2a4 protein, rat
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators
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Transcription Factors
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Angiotensin II
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Serine
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Protein-Tyrosine Kinases
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JAK2 protein, human
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Jak2 protein, rat
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Janus Kinase 2
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt