TY - JOUR
T1 - Histone lysine dimethyl-demethylase KDM3A controls pathological cardiac hypertrophy and fibrosis
AU - Zhang, Qing Jun
AU - Tran, Tram Anh T.
AU - Wang, Ming
AU - Ranek, Mark J.
AU - Kokkonen-Simon, Kristen M.
AU - Gao, Jason
AU - Luo, Xiang
AU - Tan, Wei
AU - Kyrychenko, Viktoriia
AU - Liao, Lan
AU - Xu, Jianming
AU - Hill, Joseph A
AU - Olson, Eric N
AU - Kass, David A.
AU - Martinez, Elisabeth D
AU - Liu, Zhi-Ping
N1 - Funding Information:
This work was partly funded by the National Institute of Health (RO1HL109471 and RO1CA215063 to Z.P.L., RO1CA125269 to E.D.M., RO1HL119012, R35HL135827 to D. A.K., F31HL134196 to K.M.K.-S., R01CA193455 to J.X., T35HL134639 to J.G., RO1HL120732, RO1HL128215, and RO1HL126012 to J.A.H.), by The Welch Foundation (I-1878 to E.D.M.), by Cancer Prevention and Research Institute of Texas (RP120717 to Z.P.L., RP160493 to E.D.M., RP150197 to J.X., RP11048P3 to J.A.H.), by Foundation Leducq (11CVD04 to J.A.H.), and by AHA (14SFRN20510023 and 14SFRN2067003 to J.A.H., 16GRNT3071000 to Z.P.L., and 16POST29090003 to M.J.R.).
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Left ventricular hypertrophy (LVH) is a major risk factor for cardiovascular morbidity and mortality. Pathological LVH engages transcriptional programs including reactivation of canonical fetal genes and those inducing fibrosis. Histone lysine demethylases (KDMs) are emerging regulators of transcriptional reprogramming in cancer, though their potential role in abnormal heart growth and fibrosis remains little understood. Here, we investigate gain and loss of function of an H3K9me2 specific demethylase, Kdm3a, and show it promotes LVH and fibrosis in response to pressure-overload. Cardiomyocyte KDM3A activates Timp1 transcription with pro-fibrotic activity. By contrast, a pan-KDM inhibitor, JIB-04, suppresses pressure overload-induced LVH and fibrosis. JIB-04 inhibits KDM3A and suppresses the transcription of fibrotic genes that overlap with genes downregulated in Kdm3a-KO mice versus WT controls. Our study provides genetic and biochemical evidence for a pro-hypertrophic function of KDM3A and proof-of principle for pharmacological targeting of KDMs as an effective strategy to counter LVH and pathological fibrosis.
AB - Left ventricular hypertrophy (LVH) is a major risk factor for cardiovascular morbidity and mortality. Pathological LVH engages transcriptional programs including reactivation of canonical fetal genes and those inducing fibrosis. Histone lysine demethylases (KDMs) are emerging regulators of transcriptional reprogramming in cancer, though their potential role in abnormal heart growth and fibrosis remains little understood. Here, we investigate gain and loss of function of an H3K9me2 specific demethylase, Kdm3a, and show it promotes LVH and fibrosis in response to pressure-overload. Cardiomyocyte KDM3A activates Timp1 transcription with pro-fibrotic activity. By contrast, a pan-KDM inhibitor, JIB-04, suppresses pressure overload-induced LVH and fibrosis. JIB-04 inhibits KDM3A and suppresses the transcription of fibrotic genes that overlap with genes downregulated in Kdm3a-KO mice versus WT controls. Our study provides genetic and biochemical evidence for a pro-hypertrophic function of KDM3A and proof-of principle for pharmacological targeting of KDMs as an effective strategy to counter LVH and pathological fibrosis.
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U2 - 10.1038/s41467-018-07173-2
DO - 10.1038/s41467-018-07173-2
M3 - Article
C2 - 30531796
AN - SCOPUS:85058069521
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5230
ER -