Gao Li, Guo Yudong, Liu Xiaofeng, Shang Deya, Du Yongjian
Provincial Hospital Affiliated to Shandong University, China.
Department of Neurology, The Fifth People's Hospital of Jinan, China.
Biochem Biophys Res Commun. 2017 May 20;487(1):22-27. doi: 10.1016/j.bbrc.2017.03.087. Epub 2017 Mar 20.
Increasing evidence indicate that the Krüppel-like factor KLF15, a member of Cys2/His2 zinc-finger DNA-binding proteins, attenuates cardiac hypertrophy. However, the role of KLF15 in cardiovascular system is largely unknown and the exact molecular mechanism of its protective function is not fully elucidated. In the present study, we established a mouse model of cardiac hypertrophy and found that KLF15 expression was down-regulated in hypertrophic hearts. To evaluate the roles of KLF15 in cardiac hypertrophy, we generated transgenic mice overexpressing KLF15 of KLF15 knockdown mice and subsequently induced cardiac hypertrophy. The results indicated that KLF15 overexpression protects mice from ISO-induced cardiac hypertrophy, with reduced ratios of heart weight (HW)/body weight (BW) and cross-sectional area. We also observed that KLF15 overexpression attenuated cardiac fibrosis, inhibited apoptosis and induced autophagy in cardiomyocytes compared with KLF15 knockdown mice. More importantly, we found that the KLF15 overexpression inhibited the Akt/mTOR signaling pathway. Taken together, our findings imply that KLF15 possesses potential anti-hypertrophic and anti-fibrotic functions, possibly via regulation of cell death pathways and the inhibition of Akt/mTOR axis. KLF15 may constitute an efficient candidate drug for the treatment of heart failure and other cardiovascular diseases.
越来越多的证据表明，Krüppel样因子KLF15（一种Cys2/His2锌指DNA结合蛋白家族成员）可减轻心肌肥大。然而，KLF15在心血管系统中的作用很大程度上尚不清楚，其保护功能的确切分子机制也未完全阐明。在本研究中，我们建立了心肌肥大小鼠模型，发现肥大心脏中KLF15表达下调。为了评估KLF15在心肌肥大中的作用，我们构建了过表达KLF15的转基因小鼠或KLF15基因敲低小鼠，随后诱导心肌肥大。结果表明，KLF15过表达可保护小鼠免受异丙肾上腺素诱导的心肌肥大，心脏重量（HW）/体重（BW）比值和横截面积降低。与KLF15基因敲低小鼠相比，我们还观察到KLF15过表达可减轻心肌纤维化、抑制心肌细胞凋亡并诱导自噬。更重要的是，我们发现KLF15过表达抑制了Akt/mTOR信号通路。综上所述，我们的研究结果表明，KLF15可能具有潜在的抗肥大和抗纤维化功能，可能是通过调节细胞死亡途径和抑制Akt/mTOR轴实现的。KLF15可能是治疗心力衰竭和其他心血管疾病的有效候选药物。
