Digital Theses Archive


Tesi etd-06292023-104350

Type of thesis
Targeting epigenetic changes in cardiometabolic diseases
Scientific disciplinary sector
Istituto di Scienze della Vita - PHD IN MEDICINA TRASLAZIONALE
relatore Prof. GIANNONI, ALBERTO
  • BET inhibitors
  • cardiometabolic
  • epigenetics
  • long noncoding RNA
  • sirtuins
Exam session start date
Cardiometabolic diseases, the leading pandemic of the 21st century, are characterised by epigenetic changes that persist even after cessation of noxious stimuli or despite intensive risk factor control. Although targeting epigenetic alterations has been proposed as a therapeutic strategy for other diseases (e.g., cancer, neurological and autoimmune diseases), their therapeutic potential in cardiometabolic disorders remains elusive. <br>In the present thesis, we conducted an international translational research project to investigate the epigenetic changes involved in the pathogenetic mechanisms that characterise the spectrum of cardiometabolic diseases.<br>First, we investigated the role of silent information regulator 1 (SIRT1), a histone deacetylase overexpressed during calorie restriction and whose downregulation is implicated in early cardiometabolic dysfunction. In an ex vivo setting focusing on human microcirculation, we reported that SIRT1 is part of a complex epigenetic interplay involving p66Shc and Arginase II, pro-oxidant and pro-aging proteins. We found that microvascular levels of SIRT1 are reduced in patients with obesity and in older adults. This reduction is associated with increased mitochondrial reactive oxygen species levels, reduced nitric oxide availability, and increased expression of mitochondrial respiratory chain proteins. Furthermore, ex-vivo modulation of SIRT1 rescues obesity and age-related endothelial dysfunction.<br>Second, we also investigated the potential of SIRT1-induced restoration on metabolic cardiomyopathy, a major cardiometabolic complication. Using db/db mice, an in vivo model of diabetic-related metabolic cardiomyopathy, we reported that chronic treatment with mouse recombinant SIRT1 halts and reverses metabolic cardiomyopathy by modulating the myocardial lipid signature.<br>Third, we focused on the bromodomain and extraterminal protein BRD4, an epigenetic reader that promotes transcriptional programmes involved in inflammation. We focused on a cardiometabolic phenotype characterised by the coexistence of obesity and hypertension, which we have reported to be associated with higher cardiovascular risk and impaired vascular function. In a translational setup combining human ex vivo and mouse in vivo experimental approaches, we found that therapeutic modulation of BRD4 rescued cardiometabolic vascular dysfunction and the anti-contractile properties of perivascular adipose tissue. The effects were consistent both in patients and in cardiometabolic mice, treated with high-fat diet supplementation with N-nitro-L-arginine methyl ester, and were explained by suppression of perivascular adipose tissue inflammation, likely driven by its metabolic reprogramming.<br>Finally, we explored the information contained in long noncoding RNAs, epigenetic modulators of transcriptional and post-transcriptional programmes. Using a stepwise approach based on a systematic literature search and mechanistic link to beta-cell function and insulin resistance, followed by preliminary screening in patients with and without type 2 diabetes, we investigated their ability to predict disease onset. In a prospective community-based cohort study of older adults followed for 7.5 years, we found that four long noncoding RNAs are biologically associated with incident type 2 diabetes (ANRIL, MIAT, RNCR3 and PLUTO) and are related to glucose dysregulation trajectories.<br>Leveraging an highly translational approach, this dissertation sheds light on the crucial mechanism of epigenetic changes that underlie the development of cardiometabolic diseases. Epigenetic alterations occur early in cardiometabolic disease, leaving permanent cues unaffected by gold standard therapies. Proactive approaches to risk stratification and early detection of cardiometabolic disease by exploiting the information contained in epigenetic modulators may improve patient outcomes and reduce the burden on society. Furthermore, as disease-modifying mechanisms, they may represent promising targets for epidrugs for the prevention and treatment of cardiometabolic disorders.<br>