Dataset Information

Phosphodiesterase 9A Controls Nitric-oxide Independent cGMP and Hypertrophic Heart Disease

ABSTRACT: Rat neonatal cardiac myocytes were treated with PDE5 and PDE9 inhibitor in the presence and absence of L-NAME.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Cell Culture, Fetal Cardiomyocyte

SUBMITTER: Ronald Holewinski

LAB HEAD: David A Kass

PROVIDER: PXD001585 | Pride | 2016-06-24

REPOSITORIES: Pride

ACCESS DATA

Publications

Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease.

Lee Dong I DI Zhu Guangshuo G Sasaki Takashi T Cho Gun-Sik GS Hamdani Nazha N Holewinski Ronald R Jo Su-Hyun SH Danner Thomas T Zhang Manling M Rainer Peter P PP Bedja Djahida D Kirk Jonathan A JA Ranek Mark J MJ Dostmann Wolfgang R WR Kwon Chulan C Margulies Kenneth B KB Van Eyk Jennifer E JE Paulus Walter J WJ Takimoto Eiki E Kass David A DA

Nature 20150318 7544

Cyclic guanosine monophosphate (cGMP) is a second messenger molecule that transduces nitric-oxide- and natriuretic-peptide-coupled signalling, stimulating phosphorylation changes by protein kinase G. Enhancing cGMP synthesis or blocking its degradation by phosphodiesterase type 5A (PDE5A) protects against cardiovascular disease. However, cGMP stimulation alone is limited by counter-adaptions including PDE upregulation. Furthermore, although PDE5A regulates nitric-oxide-generated cGMP, nitric oxi ...[more]

PMID: 25799991

Similar Datasets

Project description:Propionate is a common three-carbon intermediate produced from the breakdown of propiogenic substrates, such as branched-chain amino acids and odd-numbered fatty acids, and by gut bacteria. Propionate can chemically modify proteins, and if this involves histones, it may underpin a disease-relevant link between short-chain acyls and gene expression in the heart. Here, we sought to characterize how propionate-dependent modifications to histones affect cardiac gene expression and contractile function in a mouse model producing elevated levels of propionate/propionyl-CoA. An adult mouse model of propionic acidaemia (PA) was used to investigate how propionate affects histones and gene expression in the heart, an organ strongly affected in PA patients. Mass spectrometry confirmed elevated plasma propionate in 8-week PA mice, reaching levels detected in PA patient serum. Metabolomic analyses confirmed a metabolic signature of PA, but male mice had enhanced propionate processing towards -alanine. Female PA hearts had expanded end-diastolic and end-systolic volumes, and weaker systolic contractions, without major electrocardiographic changes. Ca2+ signals were deranged in female PA mice (raised diastolic Ca2+), consistent with contractile dysfunction. Differentially-expressed genes (DEGs) included Pde9a and Mme, previously linked to cardiac dysfunction. These DEGs also responded to 48-h culture of wild-type myocytes with propionate as well as butyrate, an HDAC inhibitor, suggesting a role for increased histone acetylation alongside propionylation in inducing these genes. Indeed, histone acetylation (H3K27ac) and propionylation were elevated genome-wide in the PA heart and at the promoters of Pde9a and Mme. These propionate-associated epigenetic responses were more pronounced in female PA mice. The greater prominence of epigenetic, transcriptional, and functional responses in female PA mice, despite a mostly sex-indiscriminate overall metabolic milieu, argues that histone acylation plays a defining role in the cardiac phenotype. We conclude that perturbed propionate metabolism in vivo alters histone acylation and gene expression, which impacts cardiac contractile function.

Dataset Information

Phosphodiesterase 9A Controls Nitric-oxide Independent cGMP and Hypertrophic Heart Disease

Publications

Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure