FROM BENCH TO BEDSIDE

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

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 Obiettivo del progetto (Objective)

'Cardiometabolic diseases (CMD) (such as atherosclerosis, hypertension) are the primary cause of death and disability in the Western world. Although lifestyle programmes and therapeutic approaches have significantly reduced the socio-economic burden of CMD, a large number of events still cannot be avoided (residual risk). Neointimal hyperplasia is the principal pathogenic occurrence underlying atherosclerosis, restenosis. The common feature in these disorders is de novo tissue formation in the intimal layer due to inappropriate vascular smooth muscle cell (SMC) proliferation and migration. MicroRNAs (miRs) are short, non-coding RNAs that negatively regulate the proteins expression by binding to the 3’ UTR of target mRNAs. Bioinformatic analysis predicts that each miR may regulate hundreds of targets, suggesting that they might play roles in almost every biological process, including those of the cardiovascular system. Studies are beginning to unravel their fundamental importance in vessel biology. In this grant, we propose to study the role of 2 clustered miRs, miR-143 and -145, in vessel SMC and pericyte biology, and their possible application as biomarkers of vessel diseases and as a therapeutic tool for curing occlusive vasculopathies. These 2 miRs are part of the same bicistronic unit; we previously found that they are particularly expressed in the vasculature and are able to regulate vascular homeostasis and SMC migration and proliferation: thus, their modulation may have clinical implications in the pathogenesis of vessel disease. Previous data revealed that vascular stress is associated with down-regulation of these miRs in SMCs: their modulation was found to be responsible for SMC phenotypic switch from a contractile/non proliferative to a migratory/proliferative state. We intend, therefore, to characterize the role of these miRs in atherosclerosis development with a combination of molecular biology, cellular biology, bioinformatic and proteomic techniques.'

Introduzione (Teaser)

A European study hopes to identify biomarkers and genetic links to cardiovascular diseases. Unveiling the mechanisms responsible would not only improve patient outcome but could help identify those at risk.

Descrizione progetto (Article)

Cardiometabolic diseases (CMD) such as atherosclerosis and hypertension are the primary cause of mortality and disability in developed countries. Although lifestyle programmes and therapeutic interventions have managed to reduce the socioeconomic impact of CMDs, there are still cases which cannot be avoided.

Thickening of the blood vessel wall seems to be the key underlying aetiology in atherosclerosis. The inappropriate proliferation and migration of vascular smooth muscle cells (SMCs) are the reason behind this phenomenon. Recent evidence suggested that two clustered miRNAs, miR-143 and -145 are associated with the switch of SMC phenotype from a non-proliferative to a migratory state.

Given the regulatory role of miRNAs in gene expression, the EU-funded 'Role of microRNAs 143 and 145 in cardiovascular physiology and disease: from bench to bedside' (FROM BENCH TO BEDSIDE) project aims to dissect the role of these miRNAs in different vascular pathologies. In this context, researchers developed different animal models of atherosclerosis lacking these two microRNAs.

Ongoing investigation will reveal whether these animals are more prone to develop atherosclerotic plaques. The localised distribution of specialised cells known as pericytes is also being examined alongside gene expression differences between wild-type and knockout animals.

Besides unravelling the role of miR-143/5 in atherosclerosis development, the study also hopes to establish these two miRNAs as potential biomarkers for atherosclerosis development. Additionally, an association with identified single nucleotide polymorphisms could potentially unveil a genetic predisposition to atherosclerosis.

Taken together the project findings provide novel insight into the pathology of degenerative atherosclerosis. In the long run, translation of the project results into clinical practice is expected to improve the outcome of patients with cardiovascular pathologies.