Small molecule QF84139 ameliorates cardiac hypertrophy via activating the AMPK signaling pathway
Li,Xu-xia; Zhang,Peng; Yang,Yang; Wang,Jing-jing; Zheng,Yan-jun; Tan,Ji-liang; Liu,Shen-yan; Yan,Yong-ming; Zhang,You-yi; Cheng,Yong-xian; Yang,Huang-tian
AbstractCardiac 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 mu M) 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 center dot kg(-1)center dot 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 CaMKII delta, ERK1/2, AKT, PKC epsilon, 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 AMPK alpha 2. In AMPK alpha 2-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.
Keywordcardiac hypertrophy pyrazine derivative QF84139 phenylephrine transverse aortic constriction AMPK signaling pathway PROTEIN-KINASE MAMMALIAN TARGET OVERLOAD METFORMIN MACROPHAGES MECHANISMS MEDICINE ALPHA CELLS MODEL
WOS IDWOS:000648507200001
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Document Type期刊论文
Affiliation1.[Li, Xu-xia
2.Zhang, Peng
3.Zheng, Yan-jun
4.Tan, Ji-liang
5.Liu, Shen-yan
6.Chinese Acad Sci, Univ Chinese Acad Sci, CAS Key Lab Tissue Microenvironm & Tumor, Lab Mol Cardiol,Shanghai Inst Nutr & Hlth, Shanghai 200031, Peoples R China
7.[Yang, Yang
8.Yan, Yong-ming
9.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming 650201, Yunnan, Peoples R China
10.[Wang, Jing-jing
11.Peking Univ Third Hosp, Dept Cardiol, Beijing 100191, Peoples R China
12.Peking Univ Third Hosp, Inst Vasc Med, Beijing 100191, Peoples R China
13.NHC Key Lab Cardiovasc Mol Biol & Regulatory Pept, Beijing 100191, Peoples R China
14.Minist Educ, Beijing Key Lab Cardiovasc Receptors Res, Key Lab Mol Cardiovasc Sci, Beijing 100191, Peoples R China
15.Shenzhen Univ, Hlth Sci Ctr, Sch Pharmaceut Sci, Shenzhen 518060, Peoples R China
16.Shanghai Jiao Tong Univ Affiliated Peoples Hosp 6, Dept Cardiol, Shanghai 200233, Peoples R China
17.Chinese Acad Sci, Inst Stem Cell & Regenerat, Beijing 100101, Peoples R China
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GB/T 7714
Li,Xu-xia,Zhang,Peng,Yang,Yang,et al. Small molecule QF84139 ameliorates cardiac hypertrophy via activating the AMPK signaling pathway[J]. ACTA PHARMACOLOGICA SINICA,2022,43(3):588-601.
APA Li,Xu-xia.,Zhang,Peng.,Yang,Yang.,Wang,Jing-jing.,Zheng,Yan-jun.,...&Yang,Huang-tian.(2022).Small molecule QF84139 ameliorates cardiac hypertrophy via activating the AMPK signaling pathway.ACTA PHARMACOLOGICA SINICA,43(3),588-601.
MLA Li,Xu-xia,et al."Small molecule QF84139 ameliorates cardiac hypertrophy via activating the AMPK signaling pathway".ACTA PHARMACOLOGICA SINICA 43.3(2022):588-601.
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