Interplay among H3K9-editing enzymes SUV39H1, JMJD2C and SRC-1 drives p66Shc transcription and vascular oxidative stress in obesity

Costantino, Sarah; Paneni, Francesco; Virdis, Agostino; Hussain, Shafaat; Mohammed, Shafeeq Ahmed; Capretti, G; Akhmedov, Alexander; Dalgaard, Kevin; Chiandotto, Sergio; Pospisilik, J. Andrew; Jenuwein, Thomas; Giorgio, Marco; Volpe, Massimo; Taddei, Stefano; Lüscher, Thomas F.; Cosentino, Francesco

doi:10.1093/eurheartj/ehx615

Cited by 53 publications

(48 citation statements)

References 37 publications

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“…Unbiased gene profiling and chromatin immunoprecipitation experiments showed that a complex network of chromatin remodelers, namely the methyltransferase SUV39H1, the demethylase JMJD2C and the acetyltransferase SRC-1, regulates p66 Shc transcription by inducing both demethylation and acetylation of H3K9. Selective targeting of SUV39H1, JMJD2C and SRC-1 restored endothelial NO levels and rescued obesity-induced endothelial dysfunction in genetically-obese mice [44]. Consistent with these findings, we also reported that in vivo gene silencing of p66 Shc restored endothelial insulin response by affecting the IRS-1/Akt/eNOS and NF-kB pathways [45].…”

Section: Endothelial Insulin Signalling and Vascular Dysfunctionsupporting

confidence: 83%

“…We and others have recently demonstrated that epigenetic remodelling of pro-oxidant and pro-inflammatory genes participates to endothelial IR and vascular dysfunction. Specifically, we found that the mitochondrial adaptor p66 Shc is significantly upregulated in visceral fat arteries isolated from obese patients, and correlates with oxidative stress, endothelial dysfunction and IR, as assessed by HOMA-IR [44]. Unbiased gene profiling and chromatin immunoprecipitation experiments showed that a complex network of chromatin remodelers, namely the methyltransferase SUV39H1, the demethylase JMJD2C and the acetyltransferase SRC-1, regulates p66 Shc transcription by inducing both demethylation and acetylation of H3K9.…”

Section: Endothelial Insulin Signalling and Vascular Dysfunctionmentioning

confidence: 92%

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Epigenetic processing in cardiometabolic disease

et al. 2019

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Section: Endothelial Insulin Signalling and Vascular Dysfunctionsupporting

confidence: 83%

Section: Endothelial Insulin Signalling and Vascular Dysfunctionmentioning

confidence: 92%

Epigenetic processing in cardiometabolic disease

et al. 2019

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“…Although the role of mitochondrial ROS in vascular damage is well-established, only few studies have explored the specific contribution of mitochondria-derived ROS in the pathophysiology of endothelial dysfunction in humans. Mitochondrial ROS production and membrane hyperpolarization are significantly altered in visceral fat arteries and peripheral blood mononuclear cells isolated from patients with obesity and type 2 diabetes (50,51). Furthermore, impaired endothelium-dependent vasodilation in freshly isolated arterioles from diabetic individuals is reversed by mild membrane depolarization or mitochondria-targeted antioxidants (50).…”

Section: Mitochondrial Rosmentioning

confidence: 99%

Epigenetic Control of Mitochondrial Function in the Vasculature

Mohammed

Ambrosini

Lüscher

et al. 2020

Front. Cardiovasc. Med.

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The molecular signatures of epigenetic regulation and chromatin architecture are emerging as pivotal regulators of mitochondrial function. Recent studies unveiled a complex intersection among environmental factors, epigenetic signals, and mitochondrial metabolism, ultimately leading to alterations of vascular phenotype and increased cardiovascular risk. Changing environmental conditions over the lifetime induce covalent and post-translational chemical modification of the chromatin template which sensitize the genome to establish new transcriptional programs and, hence, diverse functional states. On the other hand, metabolic alterations occurring in mitochondria affect the availability of substrates for chromatin-modifying enzymes, thus leading to maladaptive epigenetic signatures altering chromatin accessibility and gene transcription. Indeed, several components of the epigenetic machinery require intermediates of cellular metabolism (ATP, AcCoA, NADH, α-ketoglutarate) for enzymatic function. In the present review, we describe the emerging role of epigenetic modifications as fine tuners of gene transcription in mitochondrial dysfunction and vascular disease. Specifically, the following aspects are described in detail: (i) mitochondria and vascular function, (ii) mitochondrial ROS, (iii) epigenetic regulation of mitochondrial function; (iv) the role of mitochondrial metabolites as key effectors for chromatin-modifying enzymes; (v) epigenetic therapies. Understanding epigenetic routes may pave the way for new approaches to develop personalized therapies to prevent mitochondrial insufficiency and its complications.

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“…In visceral fat arteries from patients with obesity and insulin resistance, a complex chromatin network characterized by the demethylase SUV39H1, the methyltransferase JMJD2C and the acetyltransferase SRC-1 was found to be causally involved in the generation of vascular oxidative stress and endothelial dysfunction. Targeting these chromatin enzymes was indeed able to rescue obesity-related endothelial dysfunction, thus highlighting the potential relevance of chromatin modifications in the pathogenesis of vascular complications (32).…”

Section: Epigenetic Modifications and Cardiovascular Damage In Obesitmentioning

confidence: 90%

The vascular epigenome in patients with obesity and type 2 diabetes: opportunities for personalized therapies

et al. 2020

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Our genetic background provides limited information on individual risk of developing vascular complications overtime. New biological layers, namely epigenetic modifications, are now emerging as potent regulators of gene expression thus leading to altered transcriptional programs and vascular disease phenotypes. Such epigenetic modifications, defined as changes to the genome that do not involve changes in DNA sequence, are generally induced by environmental factors and poor lifestyle habits. Of note, adverse epigenetic signals acquired during life can be transmitted to the offspring thus leading to premature alterations of the epigenetic and transcriptional landscape eventually leading to early endothelial dysfunction and vascular senescence. Modifications of the epigenome play a pivotal role in the pathophysiology of cardiometabolic disturbances such as obesity and type 2 diabetes. In these patients, changes of DNA methylation and chromatin structure contribute to alter pathways regulating insulin sensitivity, glucose homeostasis, adipogenesis and vascular function. In this perspective, unveiling the ‘epigenetic landscape’ in cardiometabolic patients may help to identify new players implicated in obesity and diabetes-related vascular dysfunction and may pave the way for personalized therapies in this setting. In the present review, we discuss current knowledge of the epigenetic routes implicated in vascular damage and cardiovascular disease in patients with metabolic alterations.

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Interplay among H3K9-editing enzymes SUV39H1, JMJD2C and SRC-1 drives p66Shc transcription and vascular oxidative stress in obesity

Abstract: These results uncover a novel epigenetic mechanism underlying endothelial dysfunction in obesity. Targeting SUV39H1 may attenuate oxidative transcriptional programmes and thus prevent vascular disease in obese individuals.

Cited by 53 publications

References 37 publications

Epigenetic processing in cardiometabolic disease

Epigenetic processing in cardiometabolic disease

Epigenetic Control of Mitochondrial Function in the Vasculature

The vascular epigenome in patients with obesity and type 2 diabetes: opportunities for personalized therapies

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