Similar Datasets
Project description: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.
2018-10-09 | GSE120598 | GEO
Project description:Heart disease and failure is a leading cause of mortality worldwide. Left ventricular hypertrophy (LVH) is a major risk factor 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.
2018-10-09 | GSE120739 | GEO
Project description:Heart disease and failure is a leading cause of mortality worldwide. Left ventricular hypertrophy (LVH) and myocardial fibrosis are the major risk factor 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.
2018-10-09 | GSE120737 | GEO
Project description:Kdm3a in mouse promotes pressure overload induced cardiac hypertrophy
| PRJNA494332 | ENA
Project description:Kdm3a in mouse promotes pressure overload induced cardiac hypertrophy [RNA-seq]
| PRJNA493664 | ENA
Project description:Kdm3a in mouse promotes pressure overload induced cardiac hypertrophy [WT vs. Tg]
| PRJNA494336 | ENA
Project description:Kdm3a in mouse promotes pressure overload induced cardiac hypertrophy [WT vs. KO]
| PRJNA494337 | ENA
Project description:Aortic banding is an excellent model system to evaluate the process of development of left ventricular hypertrophy in response to hemodynamic stress. The Affymetrix GeneChip MgU74Av1 was used to analyze expression profiles of mice at different time points after surgical intervention for pressure-overload induced hypertrophy. More information about this model may be obtained at http://cardiogenomics.med.harvard.edu/groups/proj1/pages/band_home.html Keywords = Pressure overload, cardiac hypertrophy Keywords: time-course
2002-07-30 | GSE76 | GEO
Project description:Expression profiling of hearts from FVB males subjected to cardiac pressure overload by transverse aortic constriction (TAC). TAC performed on 8-10 weeks month old males and females. Hearts examined 30 weeks after surgery. Keywords: ordered
2005-06-29 | GSE2459 | GEO
Project description:Evidence from human and animal studies has documented elevated levels of lysosomal cysteine protease cathepsin K in failing hearts. Here, we hypothesized that ablation of cathepsin K mitigates pressure overload-induced cardiac hypertrophy. Cathepsin K knockout mice and their wild-type littermates were subjected to abdominal aortic constriction, resulting in cardiac remodeling (heart weight, cardiomyocyte size, left ventricular wall thickness, and end diastolic and end systolic dimensions) and decreased fractional shortening, the effects of which were significantly attenuated or ablated by cathepsin K knockout. Pressure overload dampened cardiomyocyte contractile function along with decreased resting Ca2+ levels and delayed Ca2+ clearance, which were partly resolved by cathepsin K knockout. Cardiac mammalian target of rapamycin and extracellular signal-regulated kinases (ERK) signaling cascades were upregulated by pressure overload, the effects of which were attenuated by cathepsin K knockout. In cultured H9c2 myoblast cells, silencing of cathepsin K blunted, whereas cathepsin K transfection mimicked phenylephrine-induced hypertrophic response, along with elevated phosphorylation of mammalian target of rapamycin and ERK. In addition, cathepsin K protein levels were markedly elevated in human hearts of end-stage dilated cardiomyopathy. Collectively, our data suggest that cathepsin K ablation mitigates pressure overload-induced hypertrophy, possibly via inhibition of the mammalian target of rapamycin and ERK pathways.
| S-EPMC3929275 | biostudies-literature