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Zhang, Qing-Jun; Tran, Tram Anh T; Wang, Ming; Ranek, Mark J; Kokkonen-Simon, Kristen M; Gao, Jason; Luo, Xiang; Tan, Wei; Kyrychenko, Viktoriia; Liao, Lan; Xu, Jianming; Hill, Joseph A; Olson, Eric N; Kass, David A; Martinez, Elisabeth D; Liu, Zhi-Ping
Nature communications, 12/2018, Letnik: 9, Številka: 1Journal Article
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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in: SICRIS
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