A Novel Mechanism by Which SDF-1β Protects Cardiac Cells From Palmitate-Induced Endoplasmic Reticulum Stress and Apoptosis via CXCR7 and AMPK/p38 MAPK-Mediated Interleukin-6 Generation
- Yuguang Zhao1,2,
- Yi Tan2,3,
- Shugang Xi4,
- Yunqian Li5,
- Cai Li1,
- Jiuwei Cui1,
- Xiaoqing Yan2,3,
- Xiaokun Li3,
- Guanjun Wang1,
- Wei Li1⇑ and
- Lu Cai1,2,3⇑
- 1Cancer Center, the First Hospital of Jilin University, Changchun, China
- 2Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville, Kentucky
- 3Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical College, Wenzhou, China
- 4Department of Endocrinology, the First Hospital of Jilin University, Changchun, China
- 5Department of Neurosurgery, the First Hospital of Jilin University, Changchun, China
- Corresponding authors: Wei Li, , and Lu Cai, .
Y.Z. and Y.T. contributed equally to this work.
We studied the protective effect of stromal cell-derived factor-1β (SDF-1β) 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-1β via upregulation of AMP-activated protein kinase (AMPK)–mediated p38 mitogen-activated protein kinase (MAPK) phosphorylation and interleukin-6 (IL-6) production. The SDF-1β 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-1β 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-1β’s protection from palmitate-induced apoptosis and activation of AMPK and p38 MAPK. Administration of SDF-1β 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-1β 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-1β from diabetes-induced oxidative damage, cell death, and remodeling was also associated with AMPK activation.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-1233/-/DC1.
- Received September 7, 2012.
- Accepted February 7, 2013.
- © 2013 by the American Diabetes Association.
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