Sari Flori R, Widyantoro Bambang, Thandavarayan Rajarajan A, Harima Meilei, Lakshmanan Arun Prasath, Zhang Shaosong, Muslin Anthony J, Suzuki Kenji, Kodama Makoto, Watanabe Kenichi
Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Higashijima, Niigata City, Japan.
Cell Physiol Biochem. 2011;27(5):487-96. doi: 10.1159/000329970. Epub 2011 Jun 15.
BACKGROUND/AIMS: Pressure overload stimulation is known to elicit disturbances in the endoplasmic reticulum (ER), which leads to ER stress (ERS). p38 mitogen-activated protein kinase (MAPK) plays an important role in mediating apoptotic processes, however, the roles of this kinase in activating ERS-initiated apoptosis in pressure-overloaded hearts are largely unknown.
We clarified the role of p38α MAPK in ERS-associated apoptosis by subjecting transgenic mice displaying cardiac specific dominant negative (DN) mutant p38α MAPK over-expression to seven day pressure overload.
Seven days pressure overload resulted in the same extent of cardiac hypertrophy and ERS in the wild-type (WT) and DN p38α mice compared with the sham mice. It also activated inositol-requiring enzyme (Ire)-1α and its downstream molecule, tumor necrosis factor receptor (TNFR)-associated factor (TRAF)2 in the WT and DN p38α mice compared with the sham mice. Interestingly, increased myocardial apoptosis and the up-regulation of CCAAT/enhancer binding protein homology protein (CHOP) expression compared with those in the sham mice were found in the aortic-banded WT mice, but not in the DN p38α mice.
Partial inhibition of p38α protein blocked the activation of CHOP-mediated apoptotic processes during pressure overload by partially inhibiting signaling from the Ire-1α/TRAF2 to its down-stream molecule, CHOP.
背景/目的：已知压力超负荷刺激会引发内质网（ER）紊乱，进而导致内质网应激（ERS）。p38丝裂原活化蛋白激酶（MAPK）在介导凋亡过程中起重要作用，然而，该激酶在压力超负荷心脏中激活ERS引发的凋亡中的作用尚不清楚。
通过对显示心脏特异性显性负性（DN）突变型p38α MAPK过表达的转基因小鼠进行7天压力超负荷，我们阐明了p38α MAPK在ERS相关凋亡中的作用。
与假手术小鼠相比，7天压力超负荷导致野生型（WT）和DN p38α小鼠的心脏肥大和ERS程度相同。与假手术小鼠相比，WT和DN p38α小鼠中的肌醇需求酶（Ire）-1α及其下游分子肿瘤坏死因子受体（TNFR）相关因子（TRAF）2也被激活。有趣的是，与假手术小鼠相比，在主动脉缩窄的WT小鼠中发现心肌凋亡增加和CCAAT/增强子结合蛋白同源蛋白（CHOP）表达上调，但在DN p38α小鼠中未发现。
p38α蛋白的部分抑制通过部分抑制从Ire-1α/TRAF2到其下游分子CHOP的信号传导，阻断了压力超负荷期间CHOP介导的凋亡过程的激活。
