Department of Laboratory Examination and Diagnostics, Faculty of Medicine, Oita University, Yufu-city, Oita, Japan.
Life Sci. 2010 Jul 31;87(5-6):154-61. doi: 10.1016/j.lfs.2010.06.006. Epub 2010 Jun 22.
Mechanical stress induces cardiomyocyte injury and contributes to the progression of heart failure in patients with hypertension. In this study, we investigated whether insulin exerts cardioprotective effects against mechanical stretching-induced cell injury, and whether the protective effect is influenced by high-glucose condition.
Cultured neonatal rat cardiomyocytes were plated on silicone chambers, and the cells were mechanically stretched by 15% to induce cell injury.
Mechanical stretching increased reactive oxygen species (ROS) and decreased mitochondrial inner membrane potential (DeltaPsi(m)), eventually leading to cell death by apoptosis and necrosis. Insulin activated the phosphoinositide 3 (PI3) kinase/Akt pathway and reduced apoptosis and necrosis by suppressing ROS increase and preserving DeltaPsi(m). However, high-glucose condition attenuated the insulin-induced Akt phosphorylation and cardioprotection. To investigate the mechanisms that attenuated the effects of insulin in high-glucose condition, we examined the expression of tensin homologue deleted on chromosome 10 (PTEN), which is a negative regulator of the PI3 kinase/Akt pathway. The expressions of PTEN and phosphorylated PTEN were significantly decreased by insulin, and those effects were attenuated in high-glucose condition.
The present results suggest that insulin prevents mechanical stress-induced cell injury which otherwise lead to heart failure. Furthermore, we found that high-glucose condition prevented the decrease in PTEN expression and the cardioprotective effects induced by insulin.
机械应激会导致心肌细胞损伤，并促进高血压患者心力衰竭的进展。本研究旨在探讨胰岛素是否对机械拉伸诱导的细胞损伤具有保护作用，以及这种保护作用是否受高糖条件的影响。
将新生大鼠心肌细胞种植于硅酮室，通过 15%的机械拉伸诱导细胞损伤。
机械拉伸增加了活性氧（ROS）的产生，降低了线粒体内膜电位（ΔPsi(m)），最终通过促进细胞凋亡和坏死导致细胞死亡。胰岛素激活了磷酸肌醇 3（PI3）激酶/Akt 通路，通过抑制 ROS 增加和维持 ΔPsi(m)来减少细胞凋亡和坏死。然而，高糖条件减弱了胰岛素诱导的 Akt 磷酸化和心脏保护作用。为了研究高糖条件下减弱胰岛素作用的机制，我们检测了 10 号染色体缺失的张力蛋白同系物（PTEN）的表达，PTEN 是 PI3 激酶/Akt 通路的负调节因子。胰岛素显著降低了 PTEN 和磷酸化 PTEN 的表达，而在高糖条件下，这种作用被减弱。
本研究结果表明，胰岛素可预防机械应激诱导的细胞损伤，否则会导致心力衰竭。此外，我们发现高糖条件可防止胰岛素诱导的 PTEN 表达降低和心脏保护作用减弱。
