FROM BENCH TO BEDSIDE · Role of microRNAs 143 and 145 in cardiovascular physiology and disease: from bench to bedside

Role of microRNAs 143 and 145 in cardiovascular physiology and disease: from bench to bedside

Cardiometabolic diseases (CMD) are the primary cause of death and disability in the Western world. The recent developments in genetics and genomics provide a background for investigating further this area with the aim of deepening our understanding of the atherosclerotic phenomena underlying CMD. MicroRNAs (miRNAs, miRs) are short, non-coding RNAs that negatively regulate gene expression, and are involved in cardiovascular diseases. This project proposes to study the role of 2 clustered miRNAs, miR-143 and -145, in vessel smooth muscle cell (SMCs), pericyte and endothelial biology and their possible application as biomarkers of vessel diseases and as a therapeutic tool for curing occlusive vasculopathies. Our previous data (Elia et al, 2009, Quintavalle et al, 2010, Norata et al, 2012) revealed that vascular stress is associated with down-regulation of these miRNAs in SMCs: their modulation was found to be responsible for SMC phenotypic switch from a contractile/non proliferative to a migratory/proliferative state. We intended, therefore, to characterize the role of these miRNAs in different vascular pathologies including atherosclerosis development with a combination of molecular biology, cellular biology, bioinformatic and proteomic techniques. To this end, we have characterized the role of these two genes in different animal model of atherosclerosis (miR-143/145-ApoE KO and miR-143/145-LDL-R KO). Secondly, we have elucidated the role of miR-143 and -145 in SMCs and endothelial cells communication. Finally, we have evaluated the influence of a single nucleotide polymorphism (SNP) present in the primary sequence of the human miR-143/145 cluster on the miRNA maturation, its putative molecular mechanism and the correlation of this genetic variation with cardiac complications in a cohort of coronary artery disease (CAD) patients. As today, it is estimated that cardiovascular pathologies are the first cause of death of the Western world (43%), and the major cause is the arteriosclerotic degeneration of the vessel walls. Even if recent achievements in the therapy of this disease have reduced the number of deaths and have improved the quality of life of affected patients, the estimation of people diagnosed with degenerative atherosclerosis is going to increase year by year. The early diagnosis of this pathology is the main problem, because usually the first symptoms are correlated with an already degenerated status of the vessels or with secondary problems, such as cardiac infarction, stroke or claudicatio. Just to summarize, the impact of this investigation will be particularly high for three main reasons: 1) vascular pathology represent a condition characterized by considerable morbidity and mortality; 2) its prevalence is expected to rise over the next decades; 3) there are no good treatment strategies in patients with vascular disease beside surgical intervention. Therefore, we believe that the results obtained within this project have improved the basic knowledge of the biology of vascular cells and in the next future might help to improve the outcome of patients with cardiovascular pathologies. In particular, we have been able to underlying new molecular mechanisms responsible for vessel pathologies, including atherosclerosis and the relative complication such as restenosis, but also we paved new avenues of research in order to improve the diagnosis and cure of these kinds of diseases. With no doubt, the definition of such mechanisms might help to define new therapeutic approaches based on “miRNA drugs”. Indeed, different phase I clinical trials for the treatment of cancer diseases have recently started, so there is a great probability that similar trials for cardiovascular diseases with will start very soon as well. During my re-integration period, I have been exposed to great environments, having the possibility to learn new methods and to utilize stat-of-the-art technologies. This context helped my professional maturation and the definition of my scientific profile. Finally, this Marie Curie fellowship concretely guided my re-integration in the European scientific community, giving me the opportunity to start my independent career. Reference: - Elia et al. The knockout of miR-143 and -145 alters smooth muscle cell maintenance and vascular homeostasis in mice: correlates with human disease. Cell Death Differ (2009) - Quintavalle et al. MicroRNA control of podosome formation in vascular smooth muscle cells in vivo and in vitro. J Cell Biol (2010) - Norata et al. MicroRNA 143-145 deficiency impairs vascular function. International Journal of Immunopathology and Pharmacology (2012)

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