Abstract 3274: Differential Role of TNF Receptor 1 and Receptor 2 in Myocardium Ischemic Injury: Potential Role of Adiponectin Expression
Recent experimental results suggest that activation of TNFα type 1 receptor (R1) and type 2 receptor (R2) have opposite effects on MI/R injury, but underlying molecular mechanisms remain unclear. Adiponectin (APN) is an adipocytokine with potent cardioprotective actions, and its expression/production is inhibited by TNFα in vitro. The current study determined the effect of MI on APN production and investigated whether TNFα may differentially regulate APN production through R1/R2. Adult male wild type (WT), TNFα−/−, R1−/− and R2−/− mice were subjected to MI (3d of LAD coronary ligation). Functional, histological, and biochemical analyses were performed. In WT mice, MI significantly increased plasma TNFα (P<0.01), reduced adipocyte APN mRNA (63.5±4.8% of sham MI, P<0.01), and decreased plasma APN levels (59.9±4.1% of sham MI, P<0.01). TNFα deletion significantly, but incompletely, restored APN expression/production post MI (78.8±3.9% and 74±3.8% of sham MI respectively, P<0.05 vs WT-MI). Most importantly, R1 and R2 deficiency had opposite effects on APN expression/production in MI mice. Specifically, R1−/− increased adipocyte APN mRNA and plasma APN concentrations to levels that were not only significantly higher than that seen in WT-MI mice (P<0.01), but also significantly higher than sham MI mice (129±3.8% and 134±3.9% of sham MI respectively, P<0.05). In contrast, R2−/− further exaggerated suppressive effect of MI on APN expression/production (44.9±3.2% and 41.2±3.4% of sham MI respectively, P<0.05 vs WT-MI). Notably, R1−/− mice demonstrated significantly ameliorated contractile dysfunction, attenuated myocyte hypertrophy and interstitial fibrosis in non-infarcted myocardium, and reduced apoptosis/infarct size 3d after coronary occlusion. In contrast, R2−/− had significantly exaggerated ventricular dilatation and dysfunction, exacerbated myocyte hypertrophy and interstitial fibrosis, and increased apoptosis/infarct size. These results suggest that the cardiotoxic/cardioprotective effects of TNFα R1/R2 activation might be attributable to its differential regulation of APN expression/production. Selective R1 blockade via plasma APN upregulation may be a potential therapeutic modality against ischemic injury.
This research has received full or partial funding support from the American Heart Association, Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).