Publications by authors named "Samuele Ambrosini"

7 Publications

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Disentangling the epigenetic landscape in cardiovascular patients: a path toward personalized medicine.

Minerva Cardioangiol 2020 Sep 30. Epub 2020 Sep 30.

Center for Molecular Cardiology, University of Zürich, Zürich, Switzerland -

Despite significant advances in our understanding of cardiovascular disease (CVD) we are still far from having developed breakthrough strategies to combat coronary atherosclerosis and heart failure, which account for most of CV deaths worldwide. Available cardiovascular therapies have failed to show to be equally effective in all patients, suggesting that interindividual diversity is an important factor when it comes to conceive and deliver effective personalized treatments. Genome mapping has proved useful in identifying patients who could benefit more from specific drugs depending on genetic variances; however, our genetic make-up determines only a limited part of an individual's risk profile. Recent studies have demonstrated that epigenetic changes - defined as dynamic changes of DNA and histones which do not affect DNA sequence - are key players in the pathophysiology of cardiovascular disease and may participate to delineate cardiovascular risk trajectories over the lifetime. Epigenetic modifications include changes in DNA methylation, histone modifications and non-coding RNAs and these epigenetic signals have shown to cooperate in modulating chromatin accessibility to transcription factors and gene expression. Environmental factors such as air pollution, smoking, psychosocial context and unhealthy diet regimens have shown to significantly modify the epigenome thus leading to altered transcriptional programs and CVD phenotypes. Therefore, the integration of genetic and epigenetic information might be invaluable to build individual maps of cardiovascular risk and hence, could be employed for the design of customized diagnostic and therapeutic strategies. In the present review, we discuss the growing importance of epigenetic information and its putative implications in cardiovascular precision medicine.
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http://dx.doi.org/10.23736/S0026-4725.20.05326-8DOI Listing
September 2020

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

Vasc Biol 2020 15;2(1):H19-H28. Epub 2020 May 15.

Center for Molecular Cardiology, University of Zürich, Zürich, Switzerland.

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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http://dx.doi.org/10.1530/VB-20-0001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439922PMC
May 2020

Epigenetic Remodeling in Obesity-Related Vascular Disease.

Antioxid Redox Signal 2020 Sep 9. Epub 2020 Sep 9.

Center for Molecular Cardiology, University of Zürich, Zurich, Switzerland.

The prevalence of obesity and cardiometabolic phenotypes is alarmingly increasing across the globe and is associated with atherosclerotic vascular complications and high mortality. In spite of multifactorial interventions, vascular residual risk remains high in this patient population, suggesting the need for breakthrough therapies. The mechanisms underpinning obesity-related vascular disease remain elusive and represent an intense area of investigation. Epigenetic modifications-defined as environmentally induced chemical changes of DNA and histones that do not affect DNA sequence-are emerging as a potent modulator of gene transcription in the vasculature and might significantly contribute to the development of obesity-induced endothelial dysfunction. DNA methylation and histone post-translational modifications cooperate to build complex epigenetic signals, altering transcriptional networks that are implicated in redox homeostasis, mitochondrial function, vascular inflammation, and perivascular fat homeostasis in patients with cardiometabolic disturbances. Deciphering the epigenetic landscape in the vasculature is extremely challenging due to the complexity of epigenetic signals and their function in regulating transcription. An overview of the most important epigenetic pathways is required to identify potential molecular targets to treat or prevent obesity-related endothelial dysfunction and atherosclerotic disease. This would enable the employment of precision medicine approaches in this setting. Current and future research efforts in this field entail a better definition of the vascular epigenome in obese patients as well as the unveiling of novel, cell-specific chromatin-modifying drugs that are able to erase specific epigenetic signals that are responsible for maladaptive transcriptional alterations and vascular dysfunction in obese patients.
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http://dx.doi.org/10.1089/ars.2020.8040DOI Listing
September 2020

New Mechanisms of Vascular Dysfunction in Cardiometabolic Patients: Focus on Epigenetics.

High Blood Press Cardiovasc Prev 2020 Oct 1;27(5):363-371. Epub 2020 Aug 1.

Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, 8952, Schlieren, Switzerland.

Epigenetic processing takes centre stage in cardiometabolic diseases (obesity, metabolic syndrome, type 2 diabetes, hypertension), where it participates in adiposity, inflammation, endothelial dysfunction, vascular insulin resistance and atherosclerosis. Epigenetic modifications, defined as heritable changes in gene expression that do not entail mutation in the DNA sequence, are mainly induced by environmental stimuli (stress, pollution, cigarette smoking) and are gaining considerable interest due to their causal role in cardiovascular disease, and their amenability to pharmacological intervention. Importantly, epigenetic modifications acquired during life can be transmitted to the offspring and exert their biological effects across multiple generations. Indeed, such transgenerational transmission of epigenetic signals may contribute to anticipating cardiovascular and metabolic disease phenotypes already in children and young adults. A deeper understanding of environmental factors and their effects on the epigenetic machinery and transcriptional programs is warranted to develop effective mechanism-based therapeutic strategies. The clinical application of epigenetic drugs-also known as "epi-drugs"-is currently exploding in the field of cardiovascular disease. The present review describes the main epigenetic networks underlying cardiometabolic alterations and sheds light on specific points of intervention for pharmacological reprogramming in this setting.
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http://dx.doi.org/10.1007/s40292-020-00400-2DOI Listing
October 2020

Epigenetic Control of Mitochondrial Function in the Vasculature.

Front Cardiovasc Med 2020 4;7:28. Epub 2020 Mar 4.

Center for Molecular Cardiology, University of Zürich, Zurich, Switzerland.

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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http://dx.doi.org/10.3389/fcvm.2020.00028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064473PMC
March 2020

Obesity-induced activation of JunD promotes myocardial lipid accumulation and metabolic cardiomyopathy.

Eur Heart J 2019 03;40(12):997-1008

Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, Schlieren, Switzerland.

Aims: Metabolic cardiomyopathy (MC)-characterized by intra-myocardial triglyceride (TG) accumulation and lipotoxic damage-is an emerging cause of heart failure in obese patients. Yet, its mechanisms remain poorly understood. The Activator Protein 1 (AP-1) member JunD was recently identified as a key modulator of hepatic lipid metabolism in obese mice. The present study investigates the role of JunD in obesity-induced MC.

Methods And Results: JunD transcriptional activity was increased in hearts from diet-induced obese (DIO) mice and was associated with myocardial TG accumulation and left ventricular (LV) dysfunction. Obese mice lacking JunD were protected against MC. In DIO hearts, JunD directly binds PPARγ promoter thus enabling transcription of genes involved in TG synthesis, uptake, hydrolysis, and storage (i.e. Fas, Cd36, Lpl, Plin5). Cardiac-specific overexpression of JunD in lean mice led to PPARγ activation, cardiac steatosis, and dysfunction, thereby mimicking the MC phenotype. In DIO hearts as well as in neonatal rat ventricular myocytes exposed to palmitic acid, Ago2 immunoprecipitation, and luciferase assays revealed JunD as a direct target of miR-494-3p. Indeed, miR-494-3p was down-regulated in hearts from obese mice, while its overexpression prevented lipotoxic damage by suppressing JunD/PPARγ signalling. JunD and miR-494-3p were also dysregulated in myocardial specimens from obese patients as compared with non-obese controls, and correlated with myocardial TG content, expression of PPARγ-dependent genes, and echocardiographic indices of LV dysfunction.

Conclusion: miR-494-3p/JunD is a novel molecular axis involved in obesity-related MC. These results pave the way for approaches to prevent or treat LV dysfunction in obese patients.
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http://dx.doi.org/10.1093/eurheartj/ehy903DOI Listing
March 2019

Epigenetic processing in cardiometabolic disease.

Atherosclerosis 2019 02 26;281:150-158. Epub 2018 Sep 26.

Center for Molecular Cardiology, University of Zürich, Switzerland; University Heart Center, Cardiology, University Hospital Zurich, Switzerland. Electronic address:

Albeit a consistent body of evidence supports the notion that genes influence cardiometabolic features and outcomes, the "non-genetic regulation" of this process is gaining increasing attention. Plastic chemical changes of DNA/histone complexes - known as epigenetic changes - critically determine gene activity by rapidly modifying chromatin accessibility to transcription factors. In this review, we describe the emerging role of chromatin modifications as fine tuners of gene transcription in adipogenesis, insulin resistance, macrophage polarization, immuno-metabolism, endothelial dysfunction and metabolic cardiomyopathy. Epigenetic processing participates in the dynamic interplay among different organs in the cardiometabolic patient. DNA methylation and post-translational histone modifications in both visceral and subcutaneous adipose tissue enable the transcription of genes implicated in lipo- and adipogenesis, inflammation and insulin resistance. Along the same line, complex networks of chromatin modifying enzymes are responsible for impaired nitric oxide bioavailability and defective insulin signalling in the vasculature, thus leading to reduced capillary recruitment and insulin delivery in the liver, skeletal muscle and adipose tissue. Furthermore, changes in methylation status of IL-4, IFNγ and Forkhead box P3 (Foxp3) gene loci are crucial for the polarization of immune cells, thus leading to adipose tissue inflammation and atherosclerosis. Cell-specific epigenetic information could advance our understanding of cardiometabolic processes, thus leading to individualized risk assessment and personalized therapeutic approaches in patients with cardiometabolic disturbances. The development of new chromatin modifying drugs indicates that targeting epigenetic changes is a promising approach to reduce the burden of cardiovascular disease in this setting.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.09.029DOI Listing
February 2019