Cardiac mammalian target of rapamycin (mTOR) is necessary and sufficient to prevent cardiac dysfunction in pathological hypertrophy. However, the role of cardiac mTOR in heart failure following ischemic injury remains undefined. To address this question, we used transgenic mice with cardiac-specific overexpression of mTOR (mTOR-Tg) to study ischemia-reperfusion (I/R) injury in two animal models: 1) in vivo I/R injury with transient coronary artery ligation and 2) ex vivo I/R injury in Langendorff perfused hearts with transient global ischemia. At 28 days following I/R, mortality was lower in mTOR-Tg mice than littermate controls (WT). Echocardiography and magnetic resonance imaging demonstrated that global cardiac function in mTOR-Tg mice was preserved while WT exhibited significant cardiac dysfunction. Masson's trichrome staining showed that 28 days after I/R the area of interstitial fibrosis was smaller in mTOR-Tg mice compared with WT, suggesting that adverse left ventricular (LV) remodeling is inhibited in mTOR-Tg mice. In the ex vivo I/R model, mTOR-Tg hearts demonstrated improved functional recovery compared with WT. Perfusion with Evans blue following ex vivo I/R yielded less staining in mTOR-Tg hearts than WT, indicating that mTOR overexpression inhibited necrosis during I/R injury. Expression of proinflammatory cytokines, including IL-6 and TNF-α, in mTOR-Tg hearts was lower than in WT. Consistent with this, IL-6 in the effluent post-I/R injury was lower in mTOR-Tg hearts than in WT. These findings suggest that cardiac mTOR overexpression in the heart is sufficient to provide substantial cardioprotection against I/R injury and suppress the inflammatory response.
- myocardial infarction
- LV remodeling
- transgenic mice
- heart failure
- Copyright © 2012, American Journal of Physiology - Heart and Circulatory Physiology