Network determinants of cardiovascular calcification and repositioned drug treatments

Song, Jun-Seop; Wang, Rui-Sheng; Leopold, Jane A.; Loscalzo, Joseph

doi:10.1096/fj.202001062r

Cited by 19 publications

(21 citation statements)

References 74 publications

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“…In addition to demonstrating that apoC-III enhances VIC calcification in concentrations observed in patient plasma ( 4 ), we found that apoC-III likely mediates valvular calcification via a mitochondrial dysfunction–driven inflammatory mechanism including an IL-6/BMP-2 pathway, a signaling cascade previously demonstrated as a major promoter of VIC calcification ( 2 , 12 ). Moreover, network analysis revealed connections of the apoC-III–related pathways with previously identified inflammation ( 29 ), calcification ( 29 ), and CAVD-specific ( 25 ) protein and pathway networks. Our results are in line with prior findings, suggesting that ApoC-III drives proinflammatory signaling cascades ( 32 , 33 ).…”

Section: Discussionmentioning

confidence: 79%

“…6 , A – B , respectively; complete modules in Supporting Information 3 ; all significantly enriched pathways per media in Supporting Information 4 , A – B ). In addition, the identified apoC-III–related pathways had significant connections with previously defined inflammation ( 29 ), calcification ( 29 ), and CAVD ( 25 ) modules on the protein–protein interaction (PPI) and pathway levels ( Supporting Information 5 ). Mitochondrial dysfunction and ensuing oxidative stress may elevate inflammation ( 4 ).…”

Section: Resultsmentioning

confidence: 92%

“…We used the closest distance metric d c as defined in ( 43 ) such that

where S is the set of source genes (apoC-III pathway genes), T is the set of target genes (CAVD-related pathway genes and vascular calcification–related genes), and d ( s , t ) is the network distance measured as the number of edges between nodes s and t in S and T , respectively, in the PPI network described previously. The vascular calcification–related genes, in particular, the sets of calcificasome and inflammasome genes, were taken from ( 29 ), and the CAVD-related pathways were taken from ( 25 ). The genes belonging to CAVD-related pathways were extracted from the ConsensusPathDB.…”

Section: Methodsmentioning

confidence: 99%

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ApoC-III is a novel inducer of calcification in human aortic valves

Schlotter

Freitas

Rogers

et al. 2021

Journal of Biological Chemistry

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Calcific aortic valve disease (CAVD) occurs when subpopulations of valve cells undergo specific differentiation pathways, promoting tissue fibrosis and calcification. Lipoprotein particles carry oxidized lipids that promote valvular disease, but low-density lipoprotein–lowering therapies have failed in clinical trials, and there are currently no pharmacological interventions available for this disease. Apolipoproteins are known promoters of atherosclerosis, but whether they possess pathogenic properties in CAVD is less clear. To search for a possible link, we assessed 12 apolipoproteins in nonfibrotic/noncalcific and fibrotic/calcific aortic valve tissues by proteomics and immunohistochemistry to understand if they were enriched in calcified areas. Eight apolipoproteins (apoA-I, apoA-II, apoA-IV, apoB, apoC-III, apoD, apoL-I, and apoM) were enriched in the calcific versus nonfibrotic/noncalcific tissues. Apo(a), apoB, apoC-III, apoE, and apoJ localized within the disease-prone fibrosa and colocalized with calcific regions as detected by immunohistochemistry. Circulating apoC-III on lipoprotein(a) is a potential biomarker of aortic stenosis incidence and progression, but whether apoC-III also induces aortic valve calcification is unknown. We found that apoC-III was increased in fibrotic and calcific tissues and observed within the calcification-prone fibrosa layer as well as around calcification. In addition, we showed that apoC-III induced calcification in primary human valvular cell cultures via a mitochondrial dysfunction/inflammation-mediated pathway. This study provides a first assessment of a broad array of apolipoproteins in CAVD tissues, demonstrates that specific apolipoproteins associate with valvular calcification, and implicates apoC-III as an active and modifiable driver of CAVD beyond its potential role as a biomarker.

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Section: Discussionmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 92%

“…We used the closest distance metric d c as defined in ( 43 ) such that

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

ApoC-III is a novel inducer of calcification in human aortic valves

Schlotter

Freitas

Rogers

et al. 2021

Journal of Biological Chemistry

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“…This approach has successfully identified repurposable drugs for coronary heart disease, 195 malignancies, 196 and cardiovascular calcification. 197 …”

Section: Translating To Therapies For Sars-cov-2mentioning

confidence: 99%

COVID-19 and Cardiovascular Disease

Chung

Zidar

Bristow

et al. 2021

Circulation Research

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293

266

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A pandemic of historic impact, coronavirus disease 2019 (COVID-19) has potential consequences on the cardiovascular health of millions of people who survive infection worldwide. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can infect the heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), the host cell receptor for the viral spike protein. Acute cardiac injury is a common extrapulmonary manifestation of COVID-19 with potential chronic consequences. This update provides a review of the clinical manifestations of cardiovascular involvement, potential direct SARS-CoV-2 and indirect immune response mechanisms impacting the cardiovascular system, and implications for the management of patients after recovery from acute COVID-19 infection.

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“…A recent integrated network analysis of the vascular “calcificasome” identified significant overlaps with endophenotype modules governing inflammation, thrombosis, and fibrosis [12] . Calcification in atherosclerotic aortae of ApoE-/- mice is closely linked to inflammatory macrophages, which drive osteogenic activity in early-stage atherosclerosis and precipitate pre-clinical micro-calcifications [13] .…”

mentioning

confidence: 99%