Downregulation of adiponectin induced by tumor necrosis factor α is involved in the aggravation of posttraumatic myocardial ischemia/reperfusion injury

Objective: Recent clinical observations have indicated that nonlethal mechanical trauma significantly increases myocardial infarction risk even in the presence of completely normal coronary arteries. We investigated the molecular mechanisms responsible for exacerbation of ischemic myocardial injury after nonlethal mechanical trauma with a special focus on the role of tumor necrosis factor alpha and its potential downstream effector adiponectin, a novel adipokine with anti-inflammatory and cardioprotective properties. Design: Laboratory study. Setting: University research unit. Subjects: Male adult adiponectin knockout mice and wild-type mice. Interventions: The animals were subjected to nonlethal mechanical trauma using the Noble-Collip drum (40 rpm +/- 5 mins) followed by myocardial ischemia/reperfusion injury 7 days posttrauma. We also investigated the effects of neutralizing tumor necrosis factor alpha with etanercept and exogenous adiponectin supplementation on ischemic myocardial injury after trauma. Measurements and Main Results: Trauma significantly sensitized myocardium to ischemia/reperfusion injury as evidenced by increased apoptosis, enlarged infarct size, and decreased cardiac function. Plasma adiponectin concentrations were reduced after traumatic injury (the nadir occurring 3 days posttrauma), an effect abrogated by etanercept-mediated tumor necrosis factor alpha blockade. The downregulation of adiponectin was accompanied by increased myocardial superoxide and nitric oxide generation and peroxynitrite formation. Both etanercept and exogenous adiponectin supplementation (on day 3 posttrauma or 10 mins before reperfusion on day 7 posttrauma) markedly inhibited oxidative/nitrative stress and ischemia/reperfusion injury in posttraumatic ischemic/reperfused hearts of wild-type mice, whereas only adiponectin supplementation (but not tumor necrosis factor alpha inhibition) substantially attenuated posttraumatic ischemia/reperfusion injury in adiponectin knockout mice. Conclusions: Tumor necrosis factor alpha-induced downregulation of adiponectin and the resultant enhanced oxidative/nitrative stress are involved in exacerbated posttraumatic ischemic myocardial injury. Therapeutic approaches blocking tumor necrosis factor alpha production or restoring adiponectin might have prophylactic value against secondary myocardial ischemic injury after a primary nonlethal mechanical trauma. (Crit Care Med 2011; 39:1935-1943)