The histone demethylase PHF8 represses cardiac hypertrophy upon pressure overload.
BACKGROUND
Mammalian hearts undergo hypertrophy upon pressure overload to support increased workload. Sustained hypertrophy results in cardiac decompensation and subsequently heart failure. The mechanism that prevents the development of cardiac hypertrophy is still not fully understood. Here we elucidate the anti-hypertrophic role of the histone demethylase PHF8.


RESULTS
PHF8 protein and mRNA levels were down-regulated in human failing hearts, mouse hypertrophic hearts and neonatal rat ventricle myocytes that underwent hypertrophy. Then we generated a cardiac-specific PHF8 transgenic mice, and found that PHF8 overexpression reversed cardiac dysfunction, hypertrophy and fibrosis upon pressure overload. In vivo evidence showed that PHF8 blocked protein synthesis and hypertrophic fetal genes expression. Furthermore, we found that PHF8 inhibited Akt-mTOR pathway in hypertrophic hearts and neonatal rat ventricle myocytes, and rapamycin treatment rescues the effects of PHF8 loss.


CONCLUSIONS
These results indicate that PHF8 serves as an endogenous factor that the host uses to attenuate cardiac hypertrophy upon cardiac overload. Strategies based on its enhancement might be of benefit in the treatment of hypertrophic cardiomyopathy.
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, No. 107 Cultural West Road, Lixia District, Ji׳nan City, 250012, Shandong Province, China; Department of Health care, Qianfoshan Hospital Affiliated to Shandong University, No.16766 Jingshi Road, Ji׳nan, 250012, Shangdong Province, China.
Xiaoqian
X
Liu
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, No. 107 Cultural West Road, Lixia District, Ji׳nan City, 250012, Shandong Province, China.
Xuping
X
Wang
Department of Emergency, Qianfoshan Hospital Affiliated to Shandong University, No.16766 Jingshi Road, Ji׳nan, 250012, Shangdong Province, China.
Yanping
Y
Bi
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, No. 107 Cultural West Road, Lixia District, Ji׳nan City, 250012, Shandong Province, China.
Peili
P
Bu
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, No. 107 Cultural West Road, Lixia District, Ji׳nan City, 250012, Shandong Province, China. Electronic address: zmx_1980@163.com.
Mingxiang
M
Zhang
D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D015536:Down-Regulation; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000201:enzymology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D020123:Sirolimus / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D014157:Transcription Factors; D056466:Histone Demethylases; C511934:PHF8 protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
Cardiac hypertrophy; Fibrosis; PHF8; Rapamycin; mTOR