Postnatal and Adult Aortic Heart Valves Have Distinctive Transcriptional Profiles Associated With Valve Tissue Growth and Maintenance Respectively

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.

Smooth Muscle α-Actin Expression in Mitral Valve Interstitial Cells is Important for Mediating Extracellular Matrix Remodeling

“…To examine this, we utilized the Fbn1 C1039G/+ mouse model that has previously been shown to exhibit thickened mitral valves by PND6.5 and develop systolic prolapse by 9 months of age [ 20 ]. From RNA-seq data, we have shown that Fbn1 is highly expressed in heart valves throughout life [ 34 ] and based on previous studies, it is anticipated that mRNA and protein levels do not change in mitral valves from Fbn1 C1039G/+ mice, but rather microfiber formation is impaired [ 22 ]. As shown in Figure 1 A–D, mitral valve leaflets from Fbn1 C1039G/+ pups at PND1 were grossly indistinguishable from wild type ( Fbn1 +/+ ) littermate controls ( Figure 1 B,M) by Pentachrome staining.…”

Tri‐Layered and Gel‐Like Nanofibrous Scaffolds with Anisotropic Features for Engineering Heart Valve Leaflets

“…SFRP4 is a class I antagonist of the Wnt signaling pathways and has been reported to have antiproliferative effects and reduce fibrosis. [33,34] AMCF-II (or CXCL5) is a member of the CXC chemokine family and is associated with inflammation and valve calcification. [35] Both MMP and ADAMTS are major proteinase enzymes that are required for heart valve development, repair, and remodeling.…”

Impaired Aortic Valve Growth in Type 1 Diabetes Mellitus

“…3 After embryonic maturation, these cells convert into a quiescent phenotype and in the absence of diseases maintain physiological turnover of the extracellular matrix to provide efficient function throughout life. 4 However, the mechanisms that regulate postnatal valve growth and remodelling as well as adult homeostasis are poorly understood. We believe that these findings, if confirmed, are relevant because they may indicate that the altered metabolic and endocrine milieu of type 1 diabetes may interfere with those mechanisms that maintain growth and remodelling of the aortic valve during childhood.…”