A novel mechanism by which SDF-1? protects cardiac cells from palmitate-induced endoplasmic reticulum stress and apoptosis via CXCR7 and AMPK/p38 MAPK-mediated interleukin-6 generation.
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ABSTRACT: We studied the protective effect of stromal cell-derived factor-1? (SDF-1?) on cardiac cells from lipotoxicity in vitro and diabetes in vivo. Exposure of cardiac cells to palmitate increased apoptosis by activating NADPH oxidase (NOX)-associated nitrosative stress and endoplasmic reticulum (ER) stress, which was abolished by pretreatment with SDF-1? via upregulation of AMP-activated protein kinase (AMPK)-mediated p38 mitogen-activated protein kinase (MAPK) phosphorylation and interleukin-6 (IL-6) production. The SDF-1? cardiac protection could be abolished by inhibition of AMPK, p38 MAPK, or IL-6. Activation of AMPK or addition of recombinant IL-6 recaptured a similar cardiac protection. SDF-1? receptor C-X-C chemokine receptor type 4 (CXCR4) antagonist AMD3100 or CXCR4 small interfering RNA could not, but CXCR7 small interfering RNA completely abolished SDF-1?'s protection from palmitate-induced apoptosis and activation of AMPK and p38 MAPK. Administration of SDF-1? to diabetic rats, induced by feeding a high-fat diet, followed by a small dose of streptozotocin, could significantly reduce cardiac apoptosis and increase AMPK phosphorylation along with prevention of diabetes-induced cardiac oxidative damage, inflammation, hypertrophy, and remodeling. These results showed that SDF-1? protects against palmitate-induced cardiac apoptosis, which is mediated by NOX-activated nitrosative damage and ER stress, via CXCR7, to activate AMPK/p38 MAPK-mediated IL-6 generation. The cardiac protection by SDF-1? from diabetes-induced oxidative damage, cell death, and remodeling was also associated with AMPK activation.
SUBMITTER: Zhao Y
PROVIDER: S-EPMC3712029 | biostudies-literature | 2013 Jul
REPOSITORIES: biostudies-literature
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