Our research
The research goal of our team is to unravel molecular and cellular processesunderpinning vascular and cardiac dysfunction in the setting of elevated cardiometabolic risk. The impact of this research is outlined by the notion that prevalence of obesity and type 2 diabetes (T2D) is alarmingly increasing worldwide. Although advances in therapy have reduced morbidity and mortality in T2D,cardiovascular risk is far to be eradicated and mechanism-based therapeutic approaches are in high demand. In this perspective, deciphering novel molecular networks of cardiovascular disease will be instrumental to develop effective diagnostic and therapeutic strategies.
Furthermore, the research program also aims to understand the link between environmental factors, metabolic disease and premature cardiovascular aging. These objectives are accomplished by a translational approach focused to characterize cardiovascular phenotypes through novel technologies, genetically engineered animal models and clinical studies. Our research is structured in 3 main areas:
- cardiovascular aging.
- effects of gene-environment interaction on cardiac and vascular phenotypes.
- impact of gene dysregulation on prediction of cardiovascular outcomes.
Ongoing projects
Mechanisms of cardiovascular aging.
This research line has been conceived to reveal information about the biological pathways and regulatory networks across life time that are associated with biological rather than chronological aging, focusing on the profound effects of senescence on the arterial system. Current investigations address the characterization of novel genes implicated in transcriptional programs culminating with the generation of reactive oxygen species (ROS), reduced availability of nitric oxide and inflammation. Recent data obtained in our lab are revealing common molecular pathways at the crossroad between metabolic alterations, arterial aging and cardiovascular disease.
Gene-environment interaction and cardiovascular phenotype.
In patients with metabolic diseases excessive mitochondrial ROS generation favours the activation of biochemical pathways involved in the development of cardiovascular complications. The possibility that dynamic alterations of chromatin (remodeling) may contribute to cardiovascular damage has been postulated only recently. Epigenetics refers to changes in phenotype caused by altered gene expression. These modifications can be acquired or heritable and are the expression of gene-environment interaction. Studies on genetically engineered animal models and primary cells are instrumental for the identification of detrimental epigenetic signatures eliciting early vascular and cardiac damage.
Chromatin alterations as predictors of cardiovascular outcome.
Obese and diabetic individuals represent a rather heterogeneous population characterized by metabolic phenotypes with different degrees of oxidative stress and inflammation. The most powerful strategy to reduce cardiovascular mortality is represented by early diagnosis and, hence, treatment of vascular complications. Epigenetic modifications associated with metabolic disease may contribute to the early identification of high-risk subjects. Analysis of individual epigenetic profile may provide interesting insights for the assessment of cardiovascular risk. A better understanding of the molecular cues regulating these events is of utmost importance to prevent cardiovascular disease burden in this setting.
Our translational research program - going from patients to experimental models and then back to the clinic - is designed to characterize epigenetic mechanisms regulating vascular redox and inflammatory pathways. Chromatin modifying enzymes will be screened by real time PCR arrays in the aorta of obese and diabetic mice as well as vascular tissue isolated from obese patients with IGT or T2D. Chromatin immunoprecipitation experiments (ChIP) will be employed to investigate the interaction between top-ranked epigenetic modifiers and promoter regions of pro-oxidant/inflammatory genes.
Mechanistic experiments performed in animal models will unmask the interplay between chromatin modifying enzymes in order to define upstream and downstream regulators within the epigenetic network. Once main epigenomic targets are identified, these will be tested for their potential to be reprogrammed (by means of gene silencing/overexpression, pharmacological inhibitors/activators) in human endothelial cells as well as in animal models in the attempt to blunt oxidant/inflammatory pathways and restore vascular function. Pertinent genetically engineered animal models with endothelium-specific deletion/overexpression of chromatin modifying enzymes will subsequently be employed to test the impact of different chromatin modifiers on gene transcription and vascular phenotype. Furthermore, we will address whether specific chromatin modifications are inheritable and mediate early vascular disease in the offspring.