The growing importance of epigenetics in cardiovascular medicine
Environmental factors are potent drivers of altered phenotypes and disease states. Exposure to different stimuli may indeed favour detrimental changes eliciting pathological processes in different organs, thus precipitating a cluster of comorbidities such as obesity, diabetes, aging and cardiovascular disease (CVD). These conditions often occur simultaneously and significantly aggravate human health by affecting quality of life as well as lifespan. Epigenetic modifications - defined as heritable changes in gene activity that do not affect DNA sequence - may significantly derail transcriptional programs implicated in oxidative stress, inflammation, senescence, defective stem cell functionality, and metabolic alterations, thus fostering maladaptive pathways and premature CVD. Epigenetic signatures may be classified into three main categories: (1) DNA methylation, (2) posttranslational histone modifications, and (3) RNA-based mechanisms including microRNAs and long non-coding RNAs. The complex interplay between these epigenetic signals may provide a molecular framework through which the environment can interact with the genome to alter gene expression and thereby influence cardiovascular homeostasis. We and others have previously shown that epigenetic signatures may be reversible, thus offering exciting opportunities to alter the trajectory of age and diabetes-related CVD. Indeed, plastic epigenetic changes are amenable to pharmacological intervention. Several specific compounds that target enzymes responsible for epigenetic changes [i.e. histone deacetylase (HDAC) and histone acetyltransferase (HATs) inhibitors] have been developed and are in the clinic or in clinical trials to be tested for several age-related disease.
Epigenetic regulation of cardiac and vascular repair
Over the last few years, we sought to understand the molecular mechanisms underlying epigenetic regulation of redox signalling, mitochondrial insufficiency, and angiogenic mechanisms in the setting of diabetes and ageing. Recent work has unravelled novel molecular targets implicated in age-dependent cardiovascular disease, namely endothelial progenitor cells (EPCs) dysfunction and vascular repair. In particular, we have investigated EPCs functionality in aged individuals, demonstrating that altered expression of ageing and longevity genes is a key event leading to oxidative burst and subsequent defects of EPCs migration and paracrine properties (Paneni et al. Eur Heart J 2016). Understanding the molecular cues regulating vascular healing is of paramount importance to prevent ischemic vascular complications and death in elderly as well as in patients with cardio-metabolic disturbances. Although BM-derived EPCs have shown potential value in cell therapy and regenerative medicine, early clinical studies have produced conflicting findings with absent or moderate therapeutic effects, highlighting the need for a better understanding of the underlying biological mechanisms (Figure).
A main focus of Paneni’s lab is to characterize the molecular phenotype and functionality of circulating angiogenic cells across the life course as well as in experimental and human obesity and type 2 diabetes. The identification of relevant epigenetic marks (DNA methylation, histone marks, RNAs signatures) will be invaluable to test available chromatin modifying drugs as well as antagomiRs or miRNA mimics in this setting. Our program has the ambition to provide insightful mechanistic and therapeutic advances as well as to unmask novel epigenetic biomarkers for the early detection of cardiovascular disease. These objectives will be accomplished by state-of-the-art technologies, genetically-engineered animal models and unique, deeply characterized cohorts within Switzerland and other European countries.
Specific research objectives
- To unveil new transcriptional programs orchestrating vascular and cardiac oxidative stress, inflammation and dysmetabolism;
- To characterize the epigenetic landscape, molecular phenotype and functionality of circulating angiogenic cells, and their impact on cardiac and vascular healing process. The creation of specific networks linking epigenetic status with transcriptome and protein phenotype will be instrumental to unmask epigenetically-driven networks involved in deregulation of pathways controlling cell migration, homing, as well as paracrine functions of circulating angiogenic cells.
- To understand the mechanisms of cell-cell messengers in diabetes and ageing-related EPCs dysfunction. This objective entails a scrutiny characterization of how microvescicles/microparticles, exosomes or apoptotic bodies transfer biological information to EPCs, thus affecting their phenotype.
- Paneni F, Diaz Canestro C, Libby P, Luscher TF, Camici GG. The Aging Cardiovascular System: Understanding it at the Cellular and Clinical Level. J Am Coll Cardiol. 2017 (in press).
- Paneni F; Costantino S; Kränkel N; Cosentino F; Lüscher TF. Reprogramming aging and longevity genes restores paracrine angiogenic properties of early outgrowth cells. Eur Heart J. 2016; 37:1733-7.
- Costantino S; Paneni F; Lüscher TF; Cosentino F. MicroRNA Profiling Unveils Hyperglycemic Memory in the Diabetic Heart. Eur Heart J. 2016; 37:572-6.
- Paneni F; Costantino S; Battista R; Castello L; Capretti G; Chiandotto S; Scavone G; Villano A; Pitocco D; Lanza G; Volpe M; Lüscher TF; Cosentino F. Adverse epigenetic signatures by histone methyltransferase Set7 contribute to vascular dysfunction in patients with type 2 diabetes. Circ Cardiovasc Genet. 2015; 8:150-8.
- Paneni F; Costantino S; Castello L; Battista R; Capretti G; Chiandotto S; D'Amario D; Scavone G; Villano A; Rustighi A; Crea F; Pitocco D; Lanza G; Volpe M; Del Sal G; Lüscher TF; Cosentino F. Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction: insights in patients with diabetes. Eur Heart J. 2015; 36:817-28.
- Mocharla P; Briand S; Giannotti G; Dörries C; Jakob P; Paneni F; Lüscher T; Landmesser U. AngiomiR-126 expression and secretion from circulating CD34(+) and CD14(+) PBMCs: role for proangiogenic effects and alterations in type 2 diabetics. Blood. 2013; 121:226-36.
- Paneni F; Beckman JA; Creager MA; Cosentino F. Diabetes and vascular disease: pathophysiology, clinical consequences and medical therapy. Part I. Eur Heart J. 2013; 34:2436-43.
- Beckman JA; Paneni F; Cosentino F; Creager MA. Diabetes and vascular disease: pathophysiology, clinical consequences and medical therapy. Part II. Eur Heart J. 2013; 34:2444-52.
- Paneni F; Osto E; Costantino S; Mateescu B; Briand S; Coppolino G; Perna E; Mocharla P; Akhmedov A; Kubant R; Rohrer L; Malinski T; Camici GG; Matter CM; Mechta-Grigoriou F; Volpe M; Lüscher TF; Cosentino F. Deletion of the activated protein-1 transcription factor JunD induces oxidative stress and accelerates age-related endothelial dysfunction. Circulation. 2013; 127:1229-40.
- Paneni F; Mocharla P; Akhmedov A; Costantino S; Osto E; Volpe M; Lüscher TF; Cosentino F. Gene Silencing of the Mitochondrial Adaptor p66Shc Suppresses Vascular Hyperglycemic Memory in Diabetes. Circ Res. 2012; 111:278-89.