Abstract 3506: Lymphotoxin-a is a Novel Suppressor of Adiponectin Expression and Contributes to Hypoadiponectinemia in Myocardial Ischemic/Reperfused Mice
Adiponectin (APN) is an adipocytokine with potent cardioprotective actions. Recent studies have demonstrated that APN concentration is significantly reduced following myocardial ischemia/reperfusion (MI/R). However, mechanisms responsible for MI/R-induced hypoadiponectinemia remain completely unknown. Adult male mice were subjected to 30 min MI followed by varying periods of R. Adipocyte APN mRNA expression, plasma APN level (production), and plasma concentration of TNFα, a known APN suppressor, were determined. Plasma TNFα level was significantly increased at 1h (P<0.05), peaked at 3h (1.82-fold, P<0.01), and returned to control levels 24h after R. APN expression/production began to decline 3h after R (−60.5±3.1% and −39.9±2.8%, P<0.01), reached their nadir 72h after R (−70.3±3.9% and −43.8±2.9%, P<0.01), and returned to control levels 7d after R. TNFα deficiency (TNFα−/−) significantly increased plasma APN at 3h (4.05±0.39 vs. 2.67±0.31 ng/ml in WT littermates, P0.05 vs. WT). Though multiple cytokines were significantly increased following MI/R, lymphotoxin-a (LTα) was the only one that remained elevated 24h (49±4.6 pg/ml vs. 19.5±3.6 pg/ml pre-MI/R, P<0.01) to 72 h (57±4.8 pg/ml, P<0.01) after R. LTα deficiency (LTα−/−) had no beneficial effect on APN level at 3h, but significantly increased plasma APN at 72h (3.99±0.46 vs. 2.26±0.57 ng/ml in WT littermate, P<0.01). Since TNFα receptor (TNFR) activation is required for both TNFα and LTα signaling, effects of TNFR-1 knockout on MI/R suppression of APN was determined. Compared to WT littermates, APN expression/production was significantly (P<0.01) increased before MI/R, and post-MI/R APN reduction was blocked throughout the observation period. Finally, in vitro treatment of adipocytes with TNFα and LTα, at concentrations comparable as that seen in MI/R plasma, additively inhibited APN expression/production. Collectively, our study demonstrated for the first time that LTa is a novel suppressor of APN expression and contributes to the sustained hypoadiponectinemia following MI/R. These results suggest that combining anti-TNFα with anti-LTα treatment may achieve the best cardioprotective effects in MI/R patients.
This research has received full or partial funding support from the American Heart Association, Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).