Bicuspid aortic valve patients show specific epigenetic tissue signature increasing extracellular matrix destruction

Abstract

OBJECTIVES Patients with a bicuspid aortic valve (BAV) have an increased risk for developing thoracic aortic aneurysm, which is characterized by the destruction of the elastic media of the aortic wall. Several important enzymes have been characterized to play key roles in extracellular matrix homeostasis, namely matrix metalloproteinases (MMPs). In this study, we investigated MMP-2 levels and their epigenetic regulation via the miR-29 family. METHODS Aortic tissue samples from 58 patients were collected during cardiac surgery, of which 30 presented with a BAV and 28 with a tricuspid aortic valve. Polymerase chain reaction, western blot analysis and immunohistochemistry were performed to analyse MMP-2. In addition, enzyme-linked immunosorbent assay measurements were carried out to investigate both MMP-2 and tissue inhibitor of metalloproteinase-2 levels. To examine the epigenetic regulation of aortic extracellular matrix homeostasis, we furthermore studied the expression levels of miR-29 via qRT-PCR. RESULTS Patients with a BAV were significantly younger at the time of surgery, presented significantly less frequently with arterial hypertension and displayed more often with an additional valvular disease. On a molecular level, we found that MMP-2 is increased on gene and protein level in BAV patients. Tissue inhibitor of metalloproteinase-2 levels do not differ between the groups. Interestingly, we also found that only miR-29A is significantly downregulated in BAVs. CONCLUSIONS Our findings highlight the importance of MMP-2 in the context of extracellular matrix destruction in BAV patients. We present new evidence that miR-29A is a crucial epigenetic regulator of these pathomechanistic processes and might hold promise for future translational research.

PTH‐induced EndMT via miR‐29a‐5p/GSAP/Notch1 pathway contributed to valvular calcification in rats with CKD

“…By conducting microRNA sequencing of HUVECs under PTH intervention, miR‐29a was shown to inhibit EndMT, and after stimulation of PTH, miR‐29a was observed to be decreased but was restored by PTHR1 inhibitor [PTHrP(7‐34)], indicating that PTH regulated miR‐29a via PTHR1. Meanwhile, in the valves of the CKD rat model, miR‐29a was found to be decreased compared to CTL, which was consistent with previous studies in non‐CKD VC diseases 26‐28 . Besides, the miR‐29a/b cluster was reported to suppress high glucose‐induced EndMT in human retinal microvascular endothelial cells 29 .…”

“…17 Meanwhile, in the valves of the CKD rat model, miR-29a was found to be decreased compared to CTL, which was consistent with previous studies in non-CKD VC diseases. [26][27][28] Besides, the miR-29a/b cluster was reported to suppress high glucose-induced EndMT in human retinal microvascular endothelial cells. 29 In this study, overexpression of miR-29a was shown to inhibit PTH-induced EndMT in the valves of CKD rats.…”

Structural remodelling of the heart valves extracellular matrix during embryo development

“…Disturbance of metalloproteinase (MMP) gene expression is associated with valvopathies. An increase in MMP‐2 was observed in patients with bicuspid aortic valve (Haunschild et al., 2019). Deletion of Adam17 (MMP) caused aberrant compartmentalization of versican and increased deposition of collagen, affecting postnatal viability (Wilson et al., 2013).…”

Dissecting Calcific Aortic Valve Disease—The Role, Etiology, and Drivers of Valvular Fibrosis

“…However, another histological study reported a higher grade of valvular fibrosis in stenotic BAVs vs. TAVs ( 85 ). On the molecular level, the ECM-degrading protease MMP-2 was shown to have higher expression levels in BAVs than TAVs ( 86 ). Strikingly, in all congenital semilunar valve disease, including BAV, the layered valve microstructure is disrupted ( 87 ).…”