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Kdm3a in mouse promotes pressure overload induced cardiac hypertrophy [WT vs. KO]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE120739 | GEO | 2018/10/09

REPOSITORIES: GEO

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Project description:Heart Failure with preserved Ejection Fraction (HFpEF) is a major global health problem but there are no effective therapies. The aim of this study was to assess the effects of histone deacetylase (HDAC) inhibition on cardiopulmonary structure, function, and metabolism in a large mammalian (feline) pressure overload model with HFpEF features. Male domestic short hair cats (n=26, aged 2mo), underwent either a sham procedure (n=5) or aortic constriction (n=21) using a pre-shaped band, resulting in slow-progressive pressure overload during subsequent growth. Two-months post-banding, banded cats were treated daily with either 10mg/kg suberoylanilide hydroxamic acid (b+SAHA) (n=8), an FDA approved pan-HDAC inhibitor, or vehicle (b+veh) (n=8) for 2 months. Echocardiography at 4-months post-banding revealed that b+SAHA animals had a significant reduction in left ventricular hypertrophy (LVH) and LA size vs b+veh animals. Invasively measured left ventricular end-diastolic pressure (LVEDP) and mean pulmonary arterial pressure (mPAP) were significantly elevated in b+veh and significantly reduced by b+SAHA. SAHA speeded ex-vivo myofibril relaxation independent of LVH and this effect correlated with in-vivo indices of LV relaxation. Furthermore, SAHA preserved lung structure, improved lung compliance and oxygenation, reflected by a decrease in alveolar-capillary wall thickness, alveolar-arterial oxygen gradient (A-aDO2), and intrapulmonary shunt. SAHA also reduced perivascular fluid cuffs around extra-alveolar vessels, suggesting attenuated alveolar-capillary stress failure. Acetylation proteomics revealed that SAHA altered protein acetylation in cat hearts, including histones, many mitochondrial metabolic enzymes involved in electron transport chain, TCA cycle, malate aspartate shuttle and beta oxidation, as well as cytoskeletal proteins important for muscle function. These results suggest that acetylation defects in hypertrophic stress states can be reversed by HDAC inhibitors and may be useful to improve cardiac structure and function in HFpEF patients.

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Kdm3a in mouse promotes pressure overload induced cardiac hypertrophy [WT vs. KO]

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