Abstract 1453: Cardiac-Specific Heterozygous Deletion of TSC2 Causes Compensated Hypertrophy and Protects against Ischemia/Reperfusion Injury
Mammalian target of rapamycin (mTOR) is a serine-threonine kinase that controls many cellular functions, including cell growth, protein synthesis and autophagy. Its activity was reportedly enhanced in ischemia/reperfusion. Major upstream regulators of mTOR include tuberous sclerosis complex 1 (TSC1) and TSC2 proteins, which form a herterodimeric functional complex. TSC2 acts as a GTPase-activating protein toward Rheb, thereby inhibiting mTOR through inactivation of Rheb. In order to investigate the role of TSC2 in mediating mTOR signaling and the phenotype in the heart, we generated TSC2flox/+ αMHC-Cre ± mice, cardiac specific heterozygous TSC2 deletion mice (HTD). At 3.5 months of age, TSC2 protein expression in these mice was decreased to half of that in littermate TSC2flox/+ αMHC-Cre −/− mice (WT). Left ventricular weight (LVW)/body weight (BW) and LVW/tibia length (TL) were significantly greater in HTD than in WT (LVW/BW, 3.74±0.08 vs 3.57±0.09; LVW/TL, 5.51±0.40 vs 4.77±0.35). Cross-sectional area of cardiac myocytes was significantly greater in HTD than in WT (260±10 vs 230±8 μm2). These data indicate that mild cardiac hypertrophy was developed in HTD. Echocardiographic analysis revealed normal cardiac function in HTD. The amount of interstitial fibrosis was not significantly different between HTD and WT, whereas the number of TUNEL positive myocytes was significantly less in HTD (0.05±0.005% vs 0.03±0.004%). To study the role of TSC2 in myocardial ischemia-reperfusion injury, HTD and WT underwent 45 min of ischemia and 24 hr of reperfusion. The LV infarct size/area at risk (AAR) was significantly smaller in HTD (47±2% vs 56±2%), although the size of AAR was not significantly different between HTD and WT. Analysis of signaling molecules down stream of mTOR showed 1.5 fold increase in phosphorylation of Akt, 6 fold increase in phosphoyrlation of S6K, and 1.6 fold increase in phosphorylation of 4EBP1, in HTD, suggesting that mTOR is stimulated in HTD. In summary, cardiac-specific heterozygous deletion of TSC2 causes compensated cardiac hypertrophy, inhibits apoptosis, and protects the heart from ischemia reperfusion injury. Endogenous TSC2 inhibits mTOR, thereby negatively regulating hypertrophy and cell survival in cardiac myocytes.
This research has received full or partial funding support from the American Heart Association, AHA National Center.