Fujita Ai, Takahashi-Yanaga Fumi, Morimoto Sachio, Yoshihara Tatsuya, Arioka Masaki, Igawa Kazunobu, Tomooka Katsuhiko, Hoka Sumio, Sasaguri Toshiyuki
Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Anesthesia and Critical Care Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Hypertens Res. 2017 Feb;40(2):130-139. doi: 10.1038/hr.2016.122. Epub 2016 Sep 15.
Glycogen synthase kinase-3 (GSK-3) is a crucial regulator of cardiac hypertrophy. We previously reported that 2,5-dimethylcelecoxib (DM-celecoxib), a celecoxib derivative unable to inhibit cyclooxygenase-2, prevented cardiac remodeling by activating GSK-3, resulting in lifespan prolongation in a mouse model of genetic dilated cardiomyopathy. In the present study, we investigated whether DM-celecoxib can also prevent pressure-induced cardiac remodeling and heart failure, elicited by transverse aortic constriction (TAC). Before testing the effects of DM-celecoxib, we compared the effects of TAC on the hearts of wild-type and GSK-3β hetero-deficient (GSK-3β) mice to determine the role of GSK-3 in cardiac remodeling and heart failure. GSK-3β mouse hearts exhibited more severe hypertrophy, which was characterized by accelerated interstitial fibrosis, than wild-type mouse hearts after TAC, suggesting that reduced GSK-3β activity aggravates pressure-induced left ventricular remodeling. We subsequently examined the effects of DM-celecoxib on TAC-induced cardiac remodeling. DM-celecoxib inhibited left ventricular systolic functional deterioration, and prevented left ventricular hypertrophy and fibrosis. It also activated GSK-3α and β by inhibiting Akt, suppressing the activity of β-catenin and nuclear factor of activated T-cells and thereby decreasing the expression of the Wnt/β-catenin target gene products fibronectin and matrix metalloproteinase-2. These results suggest that DM-celecoxib is clinically useful for treating pressure-induced heart diseases.
糖原合酶激酶-3（GSK-3）是心脏肥大的关键调节因子。我们之前报道过，2,5-二甲基塞来昔布（DM-塞来昔布）是一种无法抑制环氧合酶-2的塞来昔布衍生物，它通过激活GSK-3预防心脏重塑，从而延长遗传性扩张型心肌病小鼠模型的寿命。在本研究中，我们调查了DM-塞来昔布是否也能预防由主动脉缩窄（TAC）引起的压力诱导性心脏重塑和心力衰竭。在测试DM-塞来昔布的效果之前，我们比较了TAC对野生型和GSK-3β杂合缺陷（GSK-3β）小鼠心脏的影响，以确定GSK-3在心脏重塑和心力衰竭中的作用。TAC后，GSK-3β小鼠心脏表现出比野生型小鼠心脏更严重的肥大，其特征为间质纤维化加速，这表明GSK-3β活性降低会加重压力诱导的左心室重塑。随后，我们研究了DM-塞来昔布对TAC诱导的心脏重塑的影响。DM-塞来昔布抑制左心室收缩功能恶化，并预防左心室肥大和纤维化。它还通过抑制Akt激活GSK-3α和β，抑制β-连环蛋白和活化T细胞核因子的活性，从而降低Wnt/β-连环蛋白靶基因产物纤连蛋白和基质金属蛋白酶-2的表达。这些结果表明，DM-塞来昔布在临床上可用于治疗压力诱导性心脏病。
