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Perinatal iron restriction is associated with changes in neonatal cardiac function and structure in a sex-dependent manner

ABSTRACT: Iron deficiency (ID) is common during gestation and in early infancy and can alter developmental trajectories with lasting consequences on cardiovascular health. While the effects of ID and anemia on the mature heart are well documented, comparatively little is known about their effects and mechanisms on offspring cardiac development and function in the neonatal period. Female Sprague-Dawley rats were fed an iron-restricted or iron-replete diet before and during pregnancy. Cardiac function was assessed in a cohort of offspring on postnatal days (PD) 4, 14, and 28 by echocardiography; a separate cohort was euthanized for tissue collection and hearts underwent quantitative shotgun proteomic analysis. ID reduced body weight and increased relative heart weights at all time points assessed, despite recovering from anemia by PD28. Echocardiographic studies revealed unique functional impairments in ID male and female offspring, characterized by greater systolic dysfunction in the former and greater diastolic dysfunction in the latter. Proteomic analysis revealed down-regulation of structural components by ID, as well as enriched cellular responses to stress; in general, these effects were more pronounced in males. ID causes functional changes in the neonatal heart, which may reflect an inadequate or maladaptive compensation to anemia. This identifies systolic and diastolic dysfunction as comorbidities to perinatal ID anemia which may have important implications for both the short- and long-term cardiac health of newborn babies. Furthermore, therapies which improve cardiac output may mitigate the effects of ID on organ development.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Heart Ventricle

SUBMITTER: Luiz Gustavo de Almeida

LAB HEAD: Antoine Dufour

PROVIDER: PXD043588 | Pride | 2024-10-03

REPOSITORIES: Pride

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			Action	DRS
	S12269_315_Stephan_U_of_A_1_210810.raw	Raw
	S12270_316_Stephan_U_of_A_2_210810.raw	Raw
	S12271_317_Stephan_U_of_A_3_210810.raw	Raw
	S12272_318_Stephan_U_of_A_4_210810.raw	Raw
	Txt_mqpar.zip	Other

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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.

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Perinatal iron restriction is associated with changes in neonatal cardiac function and structure in a sex-dependent manner

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