The DNA methylation drift of the atherosclerotic aorta increases with lesion progression

Valencia-Morales, María del Pilar; Zaina, Silvio; Heyn, Holger; Carmona, Francisco javier García; Varol, Nuray; Sayols, Sergi; Condom, Enric; Ramírez-Ruz, José; Gómez, Antonio; Morán, Sebastian; Lund, Gertrud; Rodríguez‐Ríos, Dalia; López-González, Gladys; Ramírez-Nava, Magda; Rocha, Carmen de la; Sánchez-Flores, Alejandro; Esteller, Manel

doi:10.1186/s12920-015-0085-1

Cited by 86 publications

(69 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the diabetic condition, it is now beginning to be understood how cardiovascular complications can be linked to changes in the epigenome, both through DNA methylation [91,97] and histone modifications [42]. Studies in diabetic skeletal muscle have also demonstrated how nuclear-encoded mitochondrial protein expression can be regulated through DNA methylation [58,74].…”

Section: Discussionmentioning

confidence: 99%

Exploring the mitochondrial microRNA import pathway through Polynucleotide Phosphorylase (PNPase)

Shepherd

Hathaway

Pinti

et al. 2017

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

Cardiovascular disease is the primary cause of mortality for individuals with type 2 diabetes mellitus. During the diabetic condition, cardiovascular dysfunction can be partially attributed to molecular changes in the tissue, including alterations in microRNA (miRNA) interactions. MiRNAs have been reported in the mitochondrion and their presence may influence cellular bioenergetics, creating decrements in functional capacity. In this study, we examined the roles of Argonaute 2 (Ago2), a protein associated with cytosolic and mitochondrial miRNAs, and Polynucleotide Phosphorylase (PNPase), a protein found in the inner membrane space of the mitochondrion, to determine their role in mitochondrial miRNA import. In cardiac tissue from human and mouse models of type 2 diabetes mellitus, Ago2 protein levels were unchanged while PNPase protein expression levels were increased; also, there was an increase in the association between both proteins in the diabetic state. MiRNA-378 was found to be significantly increased in db/db mice, leading to decrements in ATP6 levels and ATP synthase activity, which was also exhibited when overexpressing PNPase in HL-1 cardiomyocytes and in HL-1 cells with stable miRNA-378 overexpression (HL-1-378). To assess potential therapeutic interventions, flow cytometry evaluated the capacity for targeting miRNA-378 species in mitochondria through antimiR treatment, revealing miRNA-378 level-dependent inhibition. Our study establishes PNPase as a contributor to mitochondrial miRNA import through the transport of miRNA-378, which may regulate bioenergetics during type 2 diabetes mellitus. Further, our data provide evidence that manipulation of PNPase levels may enhance the delivery of antimiR therapeutics to mitochondria in physiological and pathological conditions.

show abstract

Section: Discussionmentioning

confidence: 99%

Exploring the mitochondrial microRNA import pathway through Polynucleotide Phosphorylase (PNPase)

Shepherd

Hathaway

Pinti

et al. 2017

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

show abstract

“…The identified locations have been mapped to genes with known roles in the vascular wall or atherosclerosis (55,56). Globally hypomethylated chromosomal DNA is widely present in atherosclerotic plaques (57).…”

Section: Dna Methylationmentioning

confidence: 99%

Translational Perspective on Epigenetics in Cardiovascular Disease

Harst

Windt

Chambers

2017

Journal of the American College of Cardiology

View full text Add to dashboard Cite

A plethora of environmental and behavioral factors interact, resulting in changes in gene expression and providing a basis for the development and progression of cardiovascular diseases. Heterogeneity in gene expression responses among cells and individuals involves epigenetic mechanisms. Advancing technology allowing genome-scale interrogation of epigenetic marks provides a rapidly-expanding view of the complexity and diversity of the epigenome. In this review, we discuss the expanding landscape of epigenetic modifications and highlight their importance for our future understanding of disease. The epigenome provides a mechanistic link between environmental exposures and gene expression profiles ultimately leading to disease. We discuss the current evidence for transgenerational epigenetic inheritance and summarize the data linking epigenetics to cardiovascular disease. Furthermore, we review the potential targets provided by the epigenome for the development of future diagnostics, preventive strategies, and therapy for cardiovascular disease. Finally, we provide some suggestions for future directions.

show abstract

“…60 Consistently, recent follow-up uncovered many CpG loci in atherosclerotic plaques that increase in methylation with lesion progression. 61 …”

Section: Epigenetics and The Diabetic Vasculature: From Sites To Cytesmentioning

confidence: 99%

Epigenetic Changes in Diabetes and Cardiovascular Risk

Keating

Plutzky

El‐Osta

2016

Circulation Research

116

View full text Add to dashboard Cite

Cardiovascular complications remain the leading causes of morbidity and premature mortality in patients with diabetes. Studies in humans and preclinical models demonstrate lasting gene expression changes in the vasculopathies initiated by previous exposure to high glucose concentrations and the associated overproduction of reactive oxygen species. The molecular signatures of chromatin architectures that sensitize the genome to these and other cardiometabolic risk factors of the diabetic milieu are increasingly implicated in the biologic memory underlying cardiovascular complications and now widely considered as promising therapeutic targets. Atherosclerosis is a complex heterocellular disease where the contributing cell types possess distinct epigenomes shaping diverse gene expression. While the extent that pathological chromatin changes can be manipulated in human cardiovascular disease remains to be established, the clinical applicability of epigenetic interventions will be greatly advanced by a deeper understanding of the cell type-specific roles played by writers, erasers, and readers of chromatin modifications in the diabetic vasculature. This review details a current perspective of epigenetic mechanisms of macrovascular disease in diabetes, and highlights recent key descriptions of chromatinized changes associated with persistent gene expression in endothelial, smooth muscle, and circulating immune cells relevant to atherosclerosis. Furthermore we discuss the challenges associated with pharmacological targeting of epigenetic networks to correct abnormal or deregulated gene expression as a strategy to alleviate the clinical burden of diabetic cardiovascular disease.

show abstract

The DNA methylation drift of the atherosclerotic aorta increases with lesion progression

Cited by 86 publications

References 40 publications

Exploring the mitochondrial microRNA import pathway through Polynucleotide Phosphorylase (PNPase)

Exploring the mitochondrial microRNA import pathway through Polynucleotide Phosphorylase (PNPase)

Translational Perspective on Epigenetics in Cardiovascular Disease

Epigenetic Changes in Diabetes and Cardiovascular Risk

Contact Info

Product

Resources

About