Our long term interest is to study the molecular and cellular processes underpinning vascular and cardiac dysfunction in the context of obesity and diabetes. Key aspects of the research program also include the link between environmental factors, metabolic disease and premature cardiovascular ageing. These objectives are accomplished by a translational approach aimed to characterize cardiovascular disease phenotypes through novel technologies, genetically-engineered animal models and human studies.
Francesco Cosentino, MD, PhD
Prof. Francesco Cosentino obtained his MD degree in 1987 and clinical training in Internal Medicine and Cardiovascular Disease at the University of Rome. In 1991 moved to Mayo Clinic & Foundation for a cardiovascular research fellowship. During his stay at Mayo he fulfilled all the requirements for a PhD in Biomedical sciences – cardiovascular pharmacology. In 1995, he joined the Cardiovascular Division at the University Hospital of Bern as a research and clinical associate. Two years later he moved to the Division of Cardiology of Zurich University Hospital where he became lecturer and then titular professor of Cardiology. In 2000, he was appointed assistant professor of Medicine and then associate professor of Cardiology at the University of Rome “Sapienza”. Currently, he is professor of Cardiovascular Medicine at the Unit of Cardiology.
Prof. Cosentino has investigated the role of endothelium-derived nitric oxide (NO) as a regulator of vascular homeostasis and signal transduction pathways involved in diabetes-induced vascular dysfunction and oxidative stress. A novel research line of his group focuses on epigenetic mechanisms underpinning oxidative stress and inflammation in the context of cardiometabolic disease ad ageing. The relevance of his activity is outlined by outstanding international scientific collaborations with the Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, UK; Epigenetics in Human Health and Disease Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia; Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, USA; Biomedical Research Center of British Columbia University, Vancouver, Canada; Baylor College of Medicine, One Baylor Plaza, DeBakey M613, Houston, TX. Prof. Cosentino has been the recipient of several awards and prizes granted by national and international scientific institutions. He has obtained funding from Swiss and Italian research councils and private foundations. Prof. Cosentino is Board councillor of the European Society of Cardiology and Associate Editor of European Heart Journal.
Francesco Paneni, MD
Francesco Paneni was born on October 20, 1981 in Rome, Italy. Dr. Paneni obtained his M.D degree in 2006 and then started his clinical training in Cardiology at the University of Rome “Sapienza”. His clinical activity mostly focused on cardiovascular imaging and cardiac intensive care. In July 2011 he has fulfilled all the requirements for board certification in Cardiology. Then, he started a PhD program in Experimental Medicine at the University of Rome “Sapienza” where he will defend his doctoral thesis in the next months. From 2011 to 2013 he worked as research assistant in the Cardiovascular Research team of Prof. Cosentino at the University of Zurich, Switzerland. He is currently research assistant at the Unit of Cardiology. His main research topics are endothelial dysfunction, oxidative stress, diabetes, obesity, hypertension, coronary artery disease and heart failure. Dr. Paneni won the Italian Society of Cardiology Young Investigator Award 2011, “Best Swiss Oral Communication 2012 Award” at the AGLA Cardiovascular & Biology Meeting, 2012 ESC Young Investigator Award in Basic Science and 2013 Circulation Research Best Manuscript Award.
Sarah Costantino, PhD
Sarah Costantino was born on August 4, 1984 in Naples, Italy. Dr. Costantino obtained his degree in Chemistry and Pharmacy in 2008 at University of Naples "Federico II". In December 2012 she has fulfilled all the requirements for a PhD in Experimental Medicine at the Second University of Naples. Then she worked as postdoctoral research fellow in the Cardiovascular Research team of Prof. Cosentino at the University of Zurich, Switzerland. Her main research topics are vascular biology, epigenetics, diabetes, obesity and ageing. Dr. Costantino won the 2013 ESC Young Investigator Award in Basic Science.
Understanding vascular ageing
Current knowledge of the molecular pathways and biological processes underlying ageing and age-related disorders is limited. Progress in understanding the details of vascular ageing process has been hampered by the complexity of phenotypic definition of ageing and the lack of adequate biomarkers to quantify this phenomenon at the molecular level. This research line has been conceived to further characterize the biological pathways and regulatory networks across life time. Current investigations in Cosentino’s lab focus on the characterization of novel genes implicated in transcriptional programs culminating with generation of reactive oxygen species, reduced availability of endothelial nitric oxide and vascular inflammation.
Gene-environment interaction and cardiovascular phenotype in obesity/diabetes
In obese and diabetic subjects the risk of cardiovascular complications continues to increase overtime despite a multifactorial intervention including lifestyle modification, glucose-lowering drugs, anti-hypertensive agents and statins. In this perspective, mechanism-based therapeutic approaches represent a major challenge. Hyperglycemia and insulin resistance activate signalling pathways favouring the unbalance between endothelial nitric oxide (NO) availability and accumulation of reactive oxygen species (ROS). Generation of ROS rapidly inactivates NO to form peroxynitrite (ONOO-), a powerful oxidant triggering protein nitrosylation and dysfunction of key enzymes implicated in endothelial homeostasis. 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 may contribute to ROS-driven 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. The major mechanisms of epigenetic regulation are represented by DNA methylation of cytosine-paired-with-guanine (CpG) dinucleotide sequences as well as methylation or acetylation of histone proteins. Methylation and acetylation of DNA and histones are reversible processes leading to dysregulation of oxidant and inflammatory genes such as mitochondrial adaptor p66Shc as well as transcription factors JunD and NF-kB. Studies on genetically-engineered animal models and primary cells are ongoing to identify 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 several metabolic phenotypes with different degrees of oxidative stress and inflammation. The most powerful strategy to reduce cardiovascular morbidity/mortality is represented by early diagnosis and, hence, prevention 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. By translating basic science findings into clinical research we aim to find novel markers of cardiovascular risk.
Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction: insights in patients with diabetes. 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. Eur Heart J. 2014 (in press).
ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD).
Eur. Heart J. 2013 Oct;34(39):3035-87
Lack of protective role of HDL-C in patients with coronary artery disease undergoing elective coronary artery bypass grafting.
Eur. Heart J. 2013 Dec;34(46):3557-62
Deletion of the activated protein-1 transcription factor JunD induces oxidative stress and accelerates age-related endothelial dysfunction.
Circulation 2013 Mar;127(11):1229-40, e1-21
Gene silencing of the mitochondrial adaptor p66(Shc) suppresses vascular hyperglycemic memory in diabetes.
Circ. Res. 2012 Jul;111(3):278-89
Assessment of flow-mediated dilation reproducibility: a nationwide multicenter study.
J. Hypertens. 2012 Jul;30(7):1399-405
Impact of fasting glycemia and regional cerebral perfusion in diabetic subjects: a study with technetium-99m-ethyl cysteinate dimer single photon emission computed tomography.
Stroke 2009 Jan;40(1):306-8
Inhibition of protein kinase Cbeta prevents foam cell formation by reducing scavenger receptor A expression in human macrophages.
Circulation 2008 Nov;118(21):2174-82