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Our new paper entitled "Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis" explored a potential drug repositioning strategy for PCSK9 inhibitors.
https://basictranslational.onlinejacc.org/content/early/2020/06/29/j.jacbts.2020.05.004 1/N
https://basictranslational.onlinejacc.org/content/early/2020/06/29/j.jacbts.2020.05.004 1/N
There are currently no non-surgical strategies to treat or prevent CAVS. Here we show that a nonsynonymous variant in the PCSK9 gene "mimicking" the effect of PCSK9 inhibitors conferred protection against CAVS in a study sample of >12,000 cases.
Interestingly, genetic variation at the PCSK9 locus was linked with lifelong exposure to lower LDL-C levels, but not lower Lipoprotein(a) levels.
We also found that PCSK9 is highly abundant in explanted calcified human aortic valves compared to normal valves.
In vitro, human valvular interstitial cells submitted to a pro-osteogenic milieu expressed and secreted PCSK9. Inhibition of extracellular PCSK9 (with an antibody) was able to significantly reduce the calcium deposition both in normal medium, suggested a systemic and local effect
These results support those of an recent exploratory analysis of the FOURIER trial which suggested that PCSK9 inhibition could reduced CAVS events https://jamanetwork.com/journals/jamacardiology/article-abstract/2764762
