Abstract
Heart valves are organized connective tissues of high mechanical demand. They open and close over 100,000 times a day to preserve unidirectional blood flow by maintaining structure-function relationships throughout life. In affected individuals, structural failure compromises function and often leads to regurgitant blood flow and progressive heart failure. This is most common in degenerative valve disease due to age-related wear and tear, or congenital malformations. At present, the only effective treatment of valve disease is surgical repair or replacement and this is often impermanent and requires anti-coagulation therapy throughout life. Therefore, there is a critical need to discover new alternatives. A promising therapeutic area is tissue regeneration and in non-valvular tissues this requires a tightly regulated genetic “growth program” involving cell proliferation. To explore this in heart valves, we performed RNA-seq analysis to compare transcriptional profiles of aortic valve tissue isolated from mice during stages of growth (postnatal day (PND) 2) and adult maintenance (4 months). Data analysis reveals distinct mRNA profiles at each time point and pathway ontology identifies associated changes in biological functions. The PND2 aortic valve is characterized by extensive cell proliferation and expression of mRNAs related to the extracellular matrix (ECM). At 4 months, proliferation is not significant and a differential set of ECM-related genes are expressed. Interestingly there is enrichment of the defense response biological process at this later time point. Together, these data highlight the unique transcriptome of the postnatal valve during stages of growth and maturation, as well as biological functions associated with adult homeostatic valves. These studies create a platform for future work exploring the molecular programs altered in the onset of heart valve disease after birth and provide insights for the development of mechanistic-based therapies.
Highlights
The average heart beats over a billion times during one lifespan to continuously provide blood to every part of the body
In order to further define molecular profiles associated with the structural changes in postnatal and 4 month old aortic valves, we performed RNA-sequencing on isolated samples
RNA expression for samples consistently clustered by time point, as shown several ways including a Pearson’s correlation matrix, principal component analysis (PCA) and hierarchical heatmap (Figure 2A)
Summary
The average heart beats over a billion times during one lifespan to continuously provide blood to every part of the body. The complex relationship between valve cell populations and the ECM is critical for establishing and maintaining structure-function relationships throughout life This relationship begins during embryonic development, as mesenchymal precursor cells in the endocardial cushions transition towards an activated VIC phenotype and degrade primitive ECM within the cushions while secreting more diverse ECM components. Despite constant mechanical demand on the valve leaflets, turnover of valve cell populations in adult valves is relatively low [4]. It remains unclear how valve cell populations and structure-function relationships are maintained throughout life in healthy individuals, yet dysregulation of these relationships likely underlie the onset and progression of valve dysfunction and disease
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