Abstract 10411: SDF-1ß Protects Cardiac Cells From Nitrosative Damage/ER Stress-mediated Fibrosis Through CXCR7-dependent AMPK Activation and IL-6 Generation
Hyperlipidemia often occurs in the patients with obesity and type 2 diabetes, and is also primary trigger for cardiac remodeling and dysfunction. Stromal cell-derived factor-1beta (SDF-1β) was cardiac protective, but whether it also protects the cardiac cells from high fat-induced remodeling remains unknown. By using H9c2 cardiac muscle cell line, we observed the effect of SDF-1β on saturated free fatty acid-induced its fibrotic response. Exposure of H9c2 cells to palmitate at 62.5 nM for 15 h caused a significant fibrotic effect, shown by up-regulation of CTGF and TGF-β, which is by activating NADPH oxidase-associated nitrosative damage and endoplasmic reticulum (ER) stress. Pretreatment with SDF-1β significantly prohibited palmitate-induced fibrosis along with significant increases in AMPK-mediated IL-6 production. AMPK activator significantly prevents palmitate-induced cardiac fibrosis while AMPK inhibitor prohibited SDF-1β’s protective effect. Direct addition of recombinant human IL-6 to cell cultures prevented palmitate-induced fibrosis whereas IL-6 siRNA abolished the protective effect of SDF-1β. CXCR7 siRNA, but not CXCR4 siRNA abolished SDF-1β’s protective effect and above related signaling pathway. The anti-fibrotic effect of SDF-1β observed in H9C2 cells was also confirmed in the primary cultures of neonatal cardiomyocytes. These in vitro results suggest that SDF-1β prevents palmitate-induced cardiac fibrosis via its receptor CXCR7 and further activating AMPK-mediated IL-6 excretion. In vivo studies, by using type 2 diabetes models, we confirmed that high fat diet induced cardiac fibrosis, and that SDF-1β prevented high fat diet-induced cardiac fibrosis along with its activation of AMPK. This important finding opens a new road for the research of SDF-1β’s cardiac protection that is irrelevant with its well-known function of stem cell mobilization.
- © 2013 by American Heart Association, Inc.