PCSK9 and Calcific Aortic Valve Stenosis

Leopold, Jane A.

doi:10.1016/j.jacbts.2020.06.004

Cited by 6 publications

(6 citation statements)

References 8 publications

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“…Together, these results pave the way for more research that will clarify the mechanisms by which PCSK9 promotes CAVD in addition to its effect on lipid levels. 29 Our study also showed that PCSK9 acted as a downstream effector of AVCAPIR to mediate its procalcific effects. However, no significant changes in metabolic parameters (including total cholesterol, LDL, and triglycerides) were observed in AVCAPIR/ApoE DKO mice compared with ApoE –/– mice, suggesting that the lipid-lowering effects of PCSK9 inhibition were not involved in AVCAPIR deletion-elicited alleviation of calcification in AVC.…”

Section: Discussionsupporting

confidence: 60%

“…Together, these results pave the way for more research that will clarify the mechanisms by which PCSK9 promotes CAVD in addition to its effect on lipid levels. 29 Our study also showed that PCSK9 acted as a downstream effector of AVCAPIR to mediate its The PIWI-interacting RNA AVCAPIR disrupted FTO-dependent m 6 A demethylation of CD36 mRNA, thereby leading to an increase in the N 6methyladenosine of CD36 mRNA, which was then recognized by m 6 A reader IGF2BP1 (insulin-like growth factor 2 mRNA binding protein 1) and leads to increased CD36 mRNA stabilization and abundance. In turn, the upregulated CD36 stabilized and promoted the abundance of procalcific PCSK9, thereby contributing to CAVD progression.…”

Section: Discussionmentioning

confidence: 52%

“…[26][27][28] Of note, it has been gradually recognized that the presence of lower LDL-cholesterol levels seen in PCSK9 loss-of-function variation does not fully account for its protection from CAVD. 29 Therefore, exploring the direct procalcific and regulatory mechanisms of PCSK9 expression is expected to expand the treatment repertoire for CAVD.…”

Section: Clinical Perspectivementioning

confidence: 99%

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AVCAPIR: A Novel Procalcific PIWI-Interacting RNA in Calcific Aortic Valve Disease

Han,

Zhou,

et al. 2024

Circulation

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BACKGROUND: Calcification of the aortic valve leads to increased leaflet stiffness and consequently results in the development of calcific aortic valve disease (CAVD). However, the underlying molecular and cellular mechanisms of calcification remain unclear. Here, we identified a novel aortic valve calcification-associated PIWI-interacting RNA (piRNA; AVCAPIR) that increases valvular calcification and promotes CAVD progression. METHODS: Using piRNA sequencing, we identified piRNAs contributing to the pathogenesis of CAVD that we termed AVCAPIRs. High-cholesterol diet–fed ApoE –/– mice with AVCAPIR knockout were used to examine the role of AVCAPIR in aortic valve calcification (AVC). Gain- and loss-of-function assays were conducted to determine the role of AVCAPIR in the induced osteogenic differentiation of human valvular interstitial cells. To dissect the mechanisms underlying AVCAPIR-elicited procalcific effects, we performed various analyses, including an RNA pulldown assay followed by liquid chromatography-tandem mass spectrometry, methylated RNA immunoprecipitation sequencing, and RNA sequencing. RNA pulldown and RNA immunoprecipitation assays were used to study piRNA interactions with proteins. RESULTS: We found that AVCAPIR was significantly upregulated during AVC and exhibited potential diagnostic value for CAVD. AVCAPIR deletion markedly ameliorated AVC in high-cholesterol diet–fed ApoE –/– mice, as shown by reduced thickness and calcium deposition in the aortic valve leaflets, improved echocardiographic parameters (decreased peak transvalvular jet velocity and mean transvalvular pressure gradient, as well as increased aortic valve area), and diminished levels of osteogenic markers (Runx2 and Osterix) in aortic valves. These results were confirmed in osteogenic medium–induced human valvular interstitial cells. Using unbiased protein-RNA screening and molecular validation, we found that AVCAPIR directly interacts with FTO (fat mass and obesity-associated protein), subsequently blocking its N 6 -methyladenosine demethylase activity. Further transcriptomic and N 6 -methyladenosine modification epitranscriptomic screening and molecular validation confirmed that AVCAPIR hindered FTO-mediated demethylation of CD36 mRNA transcripts, thus enhancing CD36 mRNA stability through the N 6 -methyladenosine reader IGF2BP1 (insulin-like growth factor 2 mRNA binding protein). In turn, the AVCAPIR-dependent increase in CD36 stabilizes its binding partner PCSK9 (proprotein convertase subtilisin/kexin type 9), a procalcific gene, at the protein level, which accelerates the progression of AVC. CONCLUSIONS: We identified a novel piRNA that induced AVC through an RNA epigenetic mechanism and provide novel insights into piRNA-directed theranostics in CAVD.

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Section: Discussionsupporting

confidence: 60%

“…Together, these results pave the way for more research that will clarify the mechanisms by which PCSK9 promotes CAVD in addition to its effect on lipid levels. 29 Our study also showed that PCSK9 acted as a downstream effector of AVCAPIR to mediate its The PIWI-interacting RNA AVCAPIR disrupted FTO-dependent m 6 A demethylation of CD36 mRNA, thereby leading to an increase in the N 6methyladenosine of CD36 mRNA, which was then recognized by m 6 A reader IGF2BP1 (insulin-like growth factor 2 mRNA binding protein 1) and leads to increased CD36 mRNA stabilization and abundance. In turn, the upregulated CD36 stabilized and promoted the abundance of procalcific PCSK9, thereby contributing to CAVD progression.…”

Section: Discussionmentioning

confidence: 52%

Section: Clinical Perspectivementioning

confidence: 99%

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AVCAPIR: A Novel Procalcific PIWI-Interacting RNA in Calcific Aortic Valve Disease

Han,

Zhou,

et al. 2024

Circulation

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“…Loss of function due to PCSK9 R46L mutation reduces the risk of CAVS. 22 A clinical trial showed that the use of PCSK9 inhibitors decreased the hazard of new or worsening aortic stenosis. 23 But PCSK9 inhibitors mainly reduce LDL-C but not Lp(a).…”

Section: Mechanismmentioning

confidence: 99%

Pathological Mechanism and Treatment of Calcified Aortic Stenosis

Chen,

Kong,

Zhang

2024

Cardiology in Review

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Calcified aortic stenosis (AS) is one of the most common valvular heart diseases worldwide, characterized by progressive fibrocalcific remodeling and thickening of the leaflets, which ultimately leads to obstruction of blood flow. Its pathobiology is an active and complicated process, involving endothelial cell dysfunction, lipoprotein deposition and oxidation, chronic inflammation, phenotypic transformation of valve interstitial cells, neovascularization, and intravalvular hemorrhage. To date, no targeted drug has been proven to slow down or prevent disease progression. Aortic valve replacement is still the optimal treatment of AS. This article reviews the etiology, diagnosis, and management of calcified aortic stenosis and proposes novel potential therapeutic targets.

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“…Other pioneer evidence supports the upregulation of HIF-1α in normoxic conditions—mediating the calcification process in AVICs. The ubiquitin E2 ligase C (UBE2C) is a member of the Anaphase Promoting Complex/Cyclosome (APC/C), which has been reported to also bind pVHL [ 88 ]. UBE2C upregulates the endothelial–mesenchymal transition (EndMT) and endothelial AV inflammation via the stimulation of HIF-1α levels through further ubiquitination and degradation of its upstream modulator pVHL, and this was accompanied by the reduction in microRNA-483–3p (miR-483) in HAECs [ 58 ].…”

Section: The Complex Interplay Of Hypoxia Signaling Mitochondrial Dys...mentioning

confidence: 99%

The Complex Relationship between Hypoxia Signaling, Mitochondrial Dysfunction and Inflammation in Calcific Aortic Valve Disease: Insights from the Molecular Mechanisms to Therapeutic Approaches

Bouhamida

Morciano

Pedriali

et al. 2023

IJMS

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Calcific aortic valve stenosis (CAVS) is among the most common causes of cardiovascular mortality in an aging population worldwide. The pathomechanisms of CAVS are such a complex and multifactorial process that researchers are still making progress to understand its physiopathology as well as the complex players involved in CAVS pathogenesis. Currently, there is no successful and effective treatment to prevent or slow down the disease. Surgical and transcatheter valve replacement represents the only option available for treating CAVS. Insufficient oxygen availability (hypoxia) has a critical role in the pathogenesis of almost all CVDs. This process is orchestrated by the hallmark transcription factor, hypoxia-inducible factor 1 alpha subunit (HIF-1α), which plays a pivotal role in regulating various target hypoxic genes and metabolic adaptations. Recent studies have shown a great deal of interest in understanding the contribution of HIF-1α in the pathogenesis of CAVS. However, it is deeply intertwined with other major contributors, including sustained inflammation and mitochondrial impairments, which are attributed primarily to CAVS. The present review aims to cover the latest understanding of the complex interplay effect of hypoxia signaling pathways, mitochondrial dysfunction, and inflammation in CAVS. We propose further hypotheses and interconnections on the complexity of these impacts in a perspective of better understanding the pathophysiology. These interplays will be examined considering recent studies that shall help us better dissect the molecular mechanism to enable the design and development of potential future therapeutic approaches that can prevent or slow down CAVS processes.

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PCSK9 and Calcific Aortic Valve Stenosis

Abstract: Corresponding Author

Cited by 6 publications

References 8 publications

AVCAPIR: A Novel Procalcific PIWI-Interacting RNA in Calcific Aortic Valve Disease

AVCAPIR: A Novel Procalcific PIWI-Interacting RNA in Calcific Aortic Valve Disease

Pathological Mechanism and Treatment of Calcified Aortic Stenosis

The Complex Relationship between Hypoxia Signaling, Mitochondrial Dysfunction and Inflammation in Calcific Aortic Valve Disease: Insights from the Molecular Mechanisms to Therapeutic Approaches

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