P379The role of miR-29b/collagen Type I/BMP-1 pathway in angiogenesis in the ischaemic human heart

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Abstract

Purpose

Ischaemic heart disease (IHD) is the leading cause of death worldwide and can cost up to 10 billion pounds each year to the National Health Service. Current optimal therapies do not achieve complete attenuation of the deteriorating left ventricular (LV) function. Stem cell therapies may replace cells and tissue that are lost during the progression of IHD. Endogenous progenitor cells recently found in the heart have been shown to improve cardiac output in experimental models of myocardial infarction, thus demonstrating their potential therapeutic application. This study aims to understand how stem/progenitor cells can re-vascularise the injured heart tissue and promote functional tissue repair.

Methods

To date the isolation, expansion and characterisation of cardiac progenitor cells from 60 heart biopsies obtained during cardiac surgery has been achieved following well established protocols such as explants and cardiosphere-derived cell (CDC) cultures and flow cytometry. Their ability to support the development of blood vessels was determined by culturing GFP-labelled endothelial progenitors with cardiac mesenchymal progenitors. A multiple regression model was used to evaluate whether disease aetiology or co-morbidities were independent predictors of the cells pro-angiogenic potential. In addition, using a combination of pharmacological agents and techniques, such as microRNA and siRNA transfections and analysis of mRNA and protein expression the study aimed to identify molecular pathways involved in angiogenesis in the heart.

Results

The study shows that a population of cardiac mesenchymal progenitors, capable of supporting blood vessel formation have been successfully isolated and expanded from tissue biopsies of IHD patients. Their pro-angiogenic phenotype can be predicted by ischaemia and cardiovascular risk factors. In addition, these cells showed differential expression of extracellular matrix components, enzymes involved in their metabolism and intracellular modulators. Our data suggest that the miR-29b/COL1A2/BMP1 pathway is involved in angiogenesis in the ischaemic human heart.

Conclusions

Cardiac-derived mesenchymal progenitors can support new blood vessel formation, which is a prerequisite for functional tissue repair. This study identifies a molecular pathway involved in blood vessel formation in the human heart that could be manipulated to improve therapeutic angiogenesis.

Funding

NIHR programme grant to NHSBT (RP-PG-0310-1001). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

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