Abstract 201: Cardioprotective Action of Interleukin-1β in Adaptation to Cardiac Pressure Overload Stress by Activation of IGF-1/Akt Pathway
Background: Cardiac hypertrophy is initially a compensation for increased workload, but prolongation of this process is associated with a significant increase in the risk of cardiovascular events. Cardiac pressure overload reportedly induces the expression of interleukin-1β (IL-1β) and Insulin-like growth factor-1(IGF-1), whereas the actual role of IL-1βremained unclear. It has been reported that IGF-1 induces cardiac hypertrophy and inhibits cardiomyocyte apoptosis. Here, we investigated the cardioprotective action of IL-1βin adaptation to pressure-overload stress.
Methods and Results Abdominal aortas of 10-week-old male IL-1β deficient- (IL-1β − /−) and wild type- (WT)mice were banded. At day 80 after operation, the heart-to body weight (mg/g) ratio in the IL-1β − /− mice was 20 ± 1.3% lower than that of WT mice (4.7 ± 0.4 vs. WT 5.9 ± 0.4, p<0.05, N =5). Evaluation by echocardiography revealed that cardiac function in the IL-1β − /− mice was lower than in WT mice (%fractional shortening: 38±3.2% vs. WT 48±2.3%, p<0.05, n=5). The size of myocyte was smaller in IL-1β − /− mice than in WT mice. At day 4, number of TUNEL positive cells was 14.3±1.9% greater in the IL-1β − /− mice (p<0.05 vs. WT). At-day 7 and 14, phosphorylations of IGF-1 receptor and Akt was markedly attenuated, whereas, phosphorytlation of JNK and activation of caspase-3 was increased in the heart of IL-1β − /− pressure-overload mice in Western blot analysis. Cardiac myocytes and fibroblasts were subjected to cyclic stretch (12%; 60cycle/min) for 24 – 48hrs. Mechanical stretch induces expression of IL-1βand IGF-1 revealed by RT-PCR analysis. Stretch-induced IGF-1 expression was decreased in cardiac fibroblasts of IL-1β − /− mice, compared with that of WT mice. In cardiac myocytes and fibroblasts, IL-1β (10ng/ml) stimulation increased 2– 4 fold IGF-1 mRNA expression. This induction was abolished by treatment with ROS scavenger, Tempol. Treatment with JNK inhibitor diminished IL-1β-induced IGF-1 mRNA expression.
Conclusion: IL-1βexerts a cardioprotective action in the hypertrophied hearts by inducing IGF-1 and subsequent activation of the IGF-1 receptor/Akt pathway.