Small molecule QF84139 ameliorates cardiac hypertrophy via activating the AMPK signaling pathway
Small molecule QF84139 ameliorates cardiac hypertrophy via activating the AMPK signaling pathway
复制标题
小分子QF84139通过激活AMPK信号通路改善心脏肥大
DOI：
10.1038/s41401-021-00678-5
复制
发表时间：
2021-05-09
影响因子：
8.2
通讯作者：
Yang，Huang-tian
中科院分区：
文献类型：
--
作者：
Li，Xu-xia;Zhang，Peng;Yang，Huang-tian
心脏肥大是对各种刺激的一种常见的适应性反应，但长期肥大会导致心力衰竭。因此，迫切需要发现治疗心脏肥大的药物。本研究观察了新合成的吡嗪衍生物QF 84139对心肌肥厚的影响及其机制。在新生大鼠心肌细胞（NRCM）中，QF 84139（1-10 μM）预处理浓度依赖性地抑制苯肾上腺素诱导的肥大反应，其特征在于胎儿基因重新激活，增加ANP蛋白水平和扩大的心肌细胞。在成年雄性小鼠中，给予QF 84139（5-90 mg·kg-1·d-1，i. p.，持续2周）剂量依赖性逆转由心肌细胞大小、左心室质量、心脏重量和胎儿基因再激活显示的横向主动脉缩窄（TAC）诱导的心脏肥大。我们进一步发现，QF 84139选择性激活AMPK信号通路，而不影响苯肾上腺素处理的NRCM和TAC处理小鼠心脏中CaMKIIδ、ERK 1/2、AKT、PKCε和P38激酶的磷酸化。在NRCM中，QF 84139与二甲双胍对AMPK活化没有显示出累加效应，而QF 84139的抗肥大作用被AMPK抑制剂化合物C或AMPKα2的敲低消除。在AMPKα2缺陷小鼠中，QF 84139的抗肥大作用也消失。这些结果表明，QF 84139通过激活AMPK信号转导减弱PE和TAC诱导的心脏肥大。这种结构新颖的化合物将是一个有前途的先导化合物，开发有效的药物治疗心肌肥大。
Cardiac hypertrophy is a common adaptive response to a variety of stimuli, but prolonged hypertrophy leads to heart failure. Hence, discovery of agents treating cardiac hypertrophy is urgently needed. In the present study, we investigated the effects of QF84139, a newly synthesized pyrazine derivative, on cardiac hypertrophy and the underlying mechanisms. In neonatal rat cardiomyocytes (NRCMs), pretreatment with QF84139 (1–10 μM) concentration-dependently inhibited phenylephrine-induced hypertrophic responses characterized by fetal genes reactivation, increased ANP protein level and enlarged cardiomyocytes. In adult male mice, administration of QF84139 (5–90 mg·kg−1·d−1, i.p., for 2 weeks) dose-dependently reversed transverse aortic constriction (TAC)-induced cardiac hypertrophy displayed by cardiomyocyte size, left ventricular mass, heart weights, and reactivation of fetal genes. We further revealed that QF84139 selectively activated the AMPK signaling pathway without affecting the phosphorylation of CaMKIIδ, ERK1/2, AKT, PKCε, and P38 kinases in phenylephrine-treated NRCMs and in the hearts of TAC-treated mice. In NRCMs, QF84139 did not show additive effects with metformin on the AMPK activation, whereas the anti-hypertrophic effect of QF84139 was abolished by an AMPK inhibitor Compound C or knockdown of AMPKα2. In AMPKα2-deficient mice, the anti-hypertrophic effect of QF84139 was also vanished. These results demonstrate that QF84139 attenuates the PE- and TAC-induced cardiac hypertrophy via activating the AMPK signaling. This structurally novel compound would be a promising lead compound for developing effective agents for the treatment of cardiac hypertrophy.