Abstract
Background: Aortic valve calcification (AVC) is one of the most common form of heart valve disease and affects 3% of the population. No pharmacological treatments have been identified yet; however, proprotein convertase subtisilin kexin type 9 (PCSK9) inhibitors have been proposed to reduce AVC progression. We aimed to evaluate the role of PCSK9 in the aortic valve calcification. Methods: We use PCSK9 -/- and PCSK9 +/+ (WT) mice littermates (n=3-4 per group, 12 month-old female, normal diet). When aortic valves were excised, total calcium content was measured and valve interstitial cells (VIC) were isolated. Calcification assays were performed on aortic VICs, left untreated or treated with β-glycerophosphate and ascorbic acid (βGAA) for seven days on plastic dishes. MinION RNA-Seq was used to evaluate the differential expression patterns in the two groups. Results: Total calcium content of aortic valve from PCSK9 -/- mice was significantly lower than WT (1.5±0.7 vs 10.1±0.5 ng of calcium/μg of total protein, respectively; p=0.0002). Calcium quantification revealed that PCSK9 -/- VICs (untreated) were able to calcify at a less extent than WT (4.4±0.6 vs 8.0±0.5 ng/μg, respectively; p=0.0001). The βGAA treatment induced calcification in both cell types; however, a significant (p=0.01) lower calcification rate was noted in PCSK9 -/- VICs (41.9±3.6 ng/μg) compared to WT (55.9±3.5 ng/μg). RNA-Seq of VICs from WT and PCSK9 -/- mice revealed that 363 genes were differentially expressed more than two-fold (adjusted p value<0.05). Functional analysis showed that in PCSK9 -/- VICs upregulated genes coordinate p38 cascade and cytoskeleton modifications, while downregulated ones control apoptotic signalling pathway, cell proliferation and adhesion, and oxidative stress. Conclusion: These preliminary results show for the first time that PCSK9 could play a direct role in AVC and thus, therapies against PCSK9 may be beneficial to patients affected by calcific aortic valve disease.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Arteriosclerosis, Thrombosis, and Vascular Biology
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
