Genetic deletion of Kdm3a or pharmacological inhibition with JIB-04 suppressed pressure overload-induced left ventricular hypertrophy and fibrosis in mice.
Does genetic deletion of Kdm3a or pharmacological inhibition with JIB-04 prevent pressure overload-induced left ventricular hypertrophy and fibrosis in mice?
Pharmacological targeting of histone lysine demethylases (KDMs) with JIB-04 or genetic deletion of Kdm3a suppresses pressure overload-induced pathological cardiac hypertrophy and fibrosis in preclinical models.
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.
Zhang et al. (Mon,) conducted a other in Left ventricular hypertrophy and fibrosis. Kdm3a knockout and JIB-04 (pan-KDM inhibitor) vs. Wild-type controls was evaluated on Pressure overload-induced left ventricular hypertrophy and fibrosis. Genetic deletion of Kdm3a or pharmacological inhibition with JIB-04 suppressed pressure overload-induced left ventricular hypertrophy and fibrosis in mice.