Contribution of Oxidative Stress (OS) in Calcific Aortic Valve Disease (CAVD): From Pathophysiology to Therapeutic Targets

Valasciuc, Emilia; Gosav, Evelina Maria; Floria, Mariana; Costea, Claudia Florida; Dima, Nicoleta; Tudorancea, Ionuț; Mărănducă, Minela Aida; Șerban, Ionela Lăcrămioara

doi:10.3390/cells11172663

Cited by 14 publications

(7 citation statements)

References 200 publications

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“…The increasing level of reactive oxygen species (ROS) in aortic valves is a dominant hallmark and driving factor for valvular calcification. 38–40 ROS production was mitigated in the AVCAPIR/ApoE DKO aortic valves (Figure 2H). It is notable that the HCD-fed AVCAPIR/ApoE DKO female mice also experienced less AVC than their ApoE –/–- female littermates, suggesting that the procalcific effects of AVCAPIR have no obvious sex disparities (Figure S5).…”

Section: Resultsmentioning

confidence: 97%

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: Resultsmentioning

confidence: 97%

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

Han,

Zhou,

et al. 2024

Circulation

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“…41 Addressing and countering OS as an important unifying mechanism involved in the initiation and propagation of heart valve degeneration and calcification may contribute to major and effective innovations in targeted therapy. 27 We also investigated the relationship between various…”

Section: Resultsmentioning

confidence: 99%

“…1 After the AV, the MV is the second most common valve affected by HVD. 27 There is substantial evidence for the critical roles of OS in the initiation and progression of HVD. 4 In the present study, high blood levels of MDA, SOD, and AOPP were independently associated with both severe MVS and moderate/severe MVS.…”

Section: Discussionmentioning

confidence: 99%

Severity of Mitral Valve Stenosis　― Possible Relationships With Blood Oxidant Markers and Antioxidants ―

Düz

Çibuk

2024

Circ J

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phorylation, and fatty acid synthesis. 5-8 Many mechanisms, such as subcellular compartmentalization, antioxidant enzymes (e.g., catalase, glutathione peroxidase [GPx] and superoxide dismutase [SOD]), and non-enzymatic antioxidants (e.g., glutathione, vitamins C, E, and A, bilirubin, peroxiredoxins, and thioredoxin) contribute to the control of ROS concentrations. 9-11 Oxidative stress (OS) is defined as ROS concentrations beyond physiologically tolerable limits resulting from increased expression and activity of ROS-producing enzymes and/or decreased expression and activity of antioxidant mechanisms. 4 Many conditions associated with the cardiovascular system, such as endothelial dysfunction, hypertension, vascular calcification, HVD, atherosclerosis, stroke, and diabetes, have been associated with OS. 12,13 OS markers may be associated with oxidative injury in the pathophysiology of HVD, and may allow for the prediction and monitoring of the possible efficacy of therapeutic strategies designed to control these pathologies. 14 Although many studies have examined the

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“…Pathologically, CAVD is a chronic disease characterized by the thickening of the aortic valve due to the accumulation of calcium deposits, leading to a significant narrowing of the valve orifice [ 3 , 4 ]. The disease progression is steady and rapid, and although it may initially be asymptomatic, advanced stages of CAVD manifest as heart failure and even premature death [ 3 , 5 ]. At this stage, the only viable treatment option is the surgical replacement of the valve [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Indoxyl Sulfate-Induced Valve Endothelial Cell Endothelial-to-Mesenchymal Transition and Calcification in an Integrin-Linked Kinase-Dependent Manner

Delgado-Marin,

Sánchez-Esteban,

Cook-Calvete

et al. 2024

Cells

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Calcific Aortic Valve Disease (CAVD) is a significant concern for cardiovascular health and is closely associated with chronic kidney disease (CKD). Aortic valve endothelial cells (VECs) play a significant role in the onset and progression of CAVD. Previous research has suggested that uremic toxins, particularly indoxyl sulfate (IS), induce vascular calcification and endothelial dysfunction, but the effect of IS on valve endothelial cells (VECs) and its contribution to CAVD is unclear. Our results show that IS reduced human VEC viability and increased pro-calcific markers RUNX2 and alkaline phosphatase (ALP) expression. Additionally, IS-exposed VECs cultured in pro-osteogenic media showed increased calcification. Mechanistically, IS induced endothelial-to-mesenchymal transition (EndMT), evidenced by the loss of endothelial markers and increased expression of mesenchymal markers. IS triggered VEC inflammation, as revealed by NF-kB activation, and decreased integrin-linked kinase (ILK) expression. ILK overexpression reversed the loss of endothelial phenotype and RUNX2, emphasizing its relevance in the pathogenesis of CAVD in CKD. Conversely, a lower dose of IS intensified some of the effects in EndMT caused by silencing ILK. These findings imply that IS affects valve endothelium directly, contributing to CAVD by inducing EndMT and calcification, with ILK acting as a crucial modulator.

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Contribution of Oxidative Stress (OS) in Calcific Aortic Valve Disease (CAVD): From Pathophysiology to Therapeutic Targets

Cited by 14 publications

References 200 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

Severity of Mitral Valve Stenosis　― Possible Relationships With Blood Oxidant Markers and Antioxidants ―

Indoxyl Sulfate-Induced Valve Endothelial Cell Endothelial-to-Mesenchymal Transition and Calcification in an Integrin-Linked Kinase-Dependent Manner

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Contribution of Oxidative Stress (OS) in Calcific Aortic Valve Disease (CAVD): From Pathophysiology to Therapeutic Targets

Cited by 14 publications

References 200 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

Severity of Mitral Valve Stenosis ― Possible Relationships With Blood Oxidant Markers and Antioxidants ―

Indoxyl Sulfate-Induced Valve Endothelial Cell Endothelial-to-Mesenchymal Transition and Calcification in an Integrin-Linked Kinase-Dependent Manner

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Severity of Mitral Valve Stenosis　― Possible Relationships With Blood Oxidant Markers and Antioxidants ―