Pressure overload-induced cardiac hypertrophy response requires janus kinase 2-histone deacetylase 2 signaling.
Pressure overload induces cardiac hypertrophy through activation of Janus kinase 2 (Jak2), however, the underlying mechanisms remain largely unknown. In the current study, we tested whether histone deacetylase 2 (HDAC2) was involved in the process. We found that angiotensin II (Ang-II)-induced re-expression of fetal genes (Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)) in cultured cardiomyocytes was prevented by the Jak2 inhibitor AG-490 and HDAC2 inhibitor Trichostatin-A (TSA), or by Jak2/HDAC2 siRNA knockdown. On the other hand, myocardial cells with Jak2 or HDAC2 over-expression were hyper-sensitive to Ang-II. In vivo, pressure overload by transverse aorta binding (AB) induced a significant cardiac hypertrophic response as well as re-expression of ANP and BNP in mice heart, which were markedly reduced by AG-490 and TSA. Significantly, AG-490, the Jak2 inhibitor, largely suppressed pressure overload-/Ang-II-induced HDAC2 nuclear exportation in vivo and in vitro. Meanwhile, TSA or HDAC2 siRNA knockdown reduced Ang-II-induced ANP/BNP expression in Jak2 over-expressed H9c2 cardiomyocytes. Together, these results suggest that HDAC2 might be a downstream effector of Jak2 to mediate cardiac hypertrophic response by pressure overload or Ang-II.
Department of Cardiology, Shanghai Pu Dong New Area People's Hospital, Shanghai 200120, China. yingyinghuang126@126.com.
Huang
H
Ying
Department of Cardiology, Huashan Hospital of Fudan University, Shanghai 200040, China. xumaochunchina@163.com.
Mao-Chun
MC
Xu
Department of Cardiology, Shanghai Pu Dong New Area People's Hospital, Shanghai 200120, China. anjinghuahua@yeah.net.
Jing-Hua
JH
Tan
Department of Cardiology, Shanghai Pu Dong New Area People's Hospital, Shanghai 200120, China. jinghua1981126@126.com.
Jing-Hua
JH
Shen
Fudan University Shanghai Medical College Centre of Medical Experiments, Shanghai 200040, China. wanghao197136@yeah.net.
Hao
H
Wang
Department of Cardiology, Shanghai Pu Dong New Area People's Hospital, Shanghai 200120, China. drdaifuzhang163@163.com.
Dai-Fu
DF
Zhang
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology* / Q000473:pathology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011312:Pressure; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology
D006877:Hydroxamic Acids; D010446:Peptide Fragments; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain; C012589:trichostatin A; D009320:Atrial Natriuretic Factor; C062524:atrial natriuretic factor prohormone (103-125); D053614:Janus Kinase 2; D056464:Histone Deacetylase 2