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Media type:
E-Article
Title:
Molecular Mechanisms of Atherosclerosis in Metabolic Syndrome : Role of Reduced IRS2-Dependent Signaling
:
Role of Reduced IRS2-Dependent Signaling
Description:
<jats:p>
<jats:bold>
<jats:italic>Objective—</jats:italic>
</jats:bold>
The mechanisms underlying accelerated atherosclerosis in metabolic syndrome (MetS) patients remain poorly defined. In the mouse, complete disruption of insulin receptor substrate-2 (
<jats:italic>Irs2</jats:italic>
) causes insulin resistance, MetS-like manifestations, and accelerates atherosclerosis. Here, we performed human, mouse, and cell culture studies to gain insight into the contribution of defective
<jats:italic>Irs2</jats:italic>
signaling to MetS-associated alterations.
</jats:p>
<jats:p>
<jats:bold>
<jats:italic>Methods and Results—</jats:italic>
</jats:bold>
In circulating leukocytes from insulin-resistant MetS patients,
<jats:italic>Irs2</jats:italic>
and
<jats:italic>Akt2</jats:italic>
mRNA levels inversely correlate with plasma insulin levels and HOMA index and are reduced compared to insulin-sensitive MetS patients. Notably, a moderate reduction in
<jats:italic>Irs2</jats:italic>
expression in fat-fed
<jats:italic>apolipoprotein E-null</jats:italic>
mice lacking one allele of
<jats:italic>Irs2</jats:italic>
(
<jats:italic>apoE</jats:italic>
<jats:sup>−/−</jats:sup>
<jats:italic>Irs2</jats:italic>
<jats:sup>+/−</jats:sup>
) accelerates atherosclerosis compared to
<jats:italic>apoE-null</jats:italic>
controls, without affecting plaque composition. Partial
<jats:italic>Irs2</jats:italic>
inactivation also increases CD36 and SRA scavenger receptor expression and modified LDL uptake in macrophages, diminishes
<jats:italic>Akt2</jats:italic>
and
<jats:italic>Ras</jats:italic>
expression in aorta, and enhances expression of the proatherogenic cytokine MCP1 in aorta and primary vascular smooth muscle cells (VSMCs) and macrophages. Inhibition of AKT or ERK1/2, a downstream target of RAS, upregulates
<jats:italic>Mcp1</jats:italic>
in VSMCs.
</jats:p>
<jats:p>
<jats:bold>
<jats:italic>Conclusions—</jats:italic>
</jats:bold>
Enhanced levels of MCP1 resulting from reduced IRS2 expression and accompanying defects in AKT2 and Ras/ERK1/2 signaling pathways may contribute to accelerated atherosclerosis in MetS states.
</jats:p>