The incidence of diabetes and its associated micro- and macrovascular complications is greatly increasing worldwide. The most prevalent vascular complications of both type 1 and type 2 diabetes include nephropathy, retinopathy, neuropathy and cardiovascular diseases. Evidence suggests that both genetic and environmental factors are involved in these pathologies. Clinical trials have underscored the beneficial effects of intensive glycaemic control for preventing the progression of complications. Accumulating evidence suggests a key role for epigenetic mechanisms such as DNA methylation, histone post-translational modifications in chromatin, and non-coding RNAs in the complex interplay between genes and the environment. Factors associated with the pathology of diabetic complications, including hyperglycaemia, growth factors, oxidant stress and inflammatory factors can lead to dysregulation of these epigenetic mechanisms to alter the expression of pathological genes in target cells such as endothelial, vascular smooth muscle, retinal and cardiac cells, without changes in the underlying DNA sequence. Furthermore, long-term persistence of these alterations to the epigenome may be a key mechanism underlying the phenomenon of ‘metabolic memory’ and sustained vascular dysfunction despite attainment of glycaemic control. Current therapies for most diabetic complications have not been fully efficacious, and hence a study of epigenetic mechanisms that may be involved is clearly warranted as they can not only shed novel new insights into the pathology of diabetic complications, but also lead to the identification of much needed new drug targets. In this review, we highlight the emerging role of epigenetics and epigenomics in the vascular complications of diabetes and metabolic memory.
Rationale: Angiotensin II (AngII)-mediated vascular smooth muscle cell (VSMC) dysfunction plays a major role in hypertension. Long non-coding RNAs (lncRNAs) have elicited much interest, but their molecular roles in AngII actions and hypertension are unclear. Objective: To investigate the regulation and functions of a novel lncRNA “Growth factor- and pro-Inflammatory cytokine-induced Vascular cell-Expressed RNA (Giver)”, in AngII-mediated VSMC dysfunction. Methods and Results: RNA-sequencing and RT-qPCRs revealed that treatment of rat VSMC with AngII increased the expression of Giver and Nr4a3, an adjacent gene encoding a nuclear receptor. Similar changes were observed in rat and mouse aortas treated ex vivo with AngII. RNA-FISH and subcellular fractionation showed predominantly nuclear localization of Giver. AngII increased Giver expression via recruitment of Nr4a3 to Giver promoter. Microarray profiling and RT-qPCR validation in VSMC showed that Giver knockdown attenuated the expression of genes involved in oxidative stress (Nox1) and inflammation (Il6, Ccl2, Tnf), but increased Nr4a3. Conversely, endogenous Giver overexpression showed opposite effects supporting its role in oxidative stress and inflammation. ChIP assays showed Giver overexpression also increased RNA-polymerase II (Pol II) enrichment and decreased repressive histone modification H3K27me3 at Nox1 and inflammatory gene promoters. Accordingly, Giver knockdown inhibited AngII-induced oxidative stress and proliferation in rat VSMC. RNA pull-down combined with mass-spectrometry showed Giver interacts with nuclear and chromatin remodeling proteins, and corepressors including NONO. Moreover, NONO knockdown elicited similar effects as Giver knockdown on the expression of key Giver-regulated genes. Notably, GIVER and NR4A3 were increased in AngII treated human VSMC, and in arteries from hypertensive patients, but attenuated in hypertensive patients treated with Angiotensin Converting Enzyme Inhibitors or Angiotensin Receptor Blockers. Furthermore, human GIVER also exhibits partial functional conservation with rat Giver. Conclusions: Giver and its regulator Nr4a3 are important players in AngII-mediated VSMC dysfunction and could be novel targets for anti-hypertensive therapy.
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