Kdm3a in mouse promotes pressure overload induced cardiac hypertrophy [RNA-seq]

Heart disease and failure is a leading cause of mortality worldwide. Left ventricular hypertrophy (LVH) and myocardial fibrosis are major risk factors for cardiovascular morbidity and mortality and the development of heart failure. Pathological LVH induced by sustained pressure-overload engages transcriptional programs including reactivation of canonical fetal genes and those inducing fibrosis. Histone lysine demethylases (KDMs) are emerging potent regulators of transcriptional reprogramming in cancer, though their potential role in abnormal growth and fibrosis in heart disease remains little understood. Here, we investigated gain and loss of function of an H3K9me2 specific demethylase, Kdm3a, in myocytes and in vivo, and show it promotes LVH and myocardial fibrosis in response to pressure-overload. Cardiomyocyte KDM3A activates the transcription of tissue-inhibitor of MMP type 1 (Timp1) with pro-fibrotic activity. By contrast, a pan-KDM inhibitor, JIB-04, suppresses TAC-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. There are four samples in this project: sham+veh, sham+JIB-04, TAC+Veh, TAC+JIB-04. Sham+Veh is used as a control to show the normal gene expression profile in mouse heart tissue. Sham+JIB-04 is used to show the change of gene expression caused by JIB-04 under baseline condition. TAC+Veh results show the gene expression change caused by pressure overload. TAC+JIB-04 results show the gene expressional change caused by JIB-04 under pressure overload condition.