Arterial calcification: A review of mechanisms, animal models, and the prospects for therapy

Wallin, Reidar; Wajih, Nadeem; Greenwood, G. Todd; Sane, David C.

doi:10.1002/med.1010

Cited by 200 publications

(47 citation statements)

References 223 publications

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“…20,56 LPC induces apoptosis in a variety of cell types. When LPC was applied to rat pancreatic AR42J cells, there was an increase in DNA fragmentation as concentrations of LPC increased up to 25 μM.…”

Section: Discussionmentioning

confidence: 99%

Differential Aortic and Mitral Valve Interstitial Cell Mineralization and the Induction of Mineralization by Lysophosphatidylcholine In Vitro

Wiltz

Han

Wilson

et al. 2014

Cardiovasc Eng Tech

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Purpose Calcific aortic valve disease (CAVD) is a serious condition with vast uncertainty regarding the precise mechanism leading to valve calcification. This study was undertaken to examine the role of the lipid lysophosphatidylcholine (LPC) in a comparison of aortic and mitral valve cellular mineralization. Methods The proportion of LPC in differentially calcified regions of diseased aortic valves was determined using thin layer chromatography (TLC). Next, porcine valvular interstitial cells (pVICs) from the aortic (paVICs) and mitral valve (pmVICs) were cultured with LPC (10−1 – 105 nM) and analyzed for cellular mineralization, alkaline phosphatase activity (ALPa), proliferation, and apoptosis. Results TLC showed a higher percentage of LPC in calcified regions of tissue compared to non-calcified regions. In pVIC cultures, with the exception of 105 nM LPC, increasing concentrations of LPC led to an increase in phosphate mineralization. Increased levels of calcium content were exhibited at 104 nm LPC application compared to baseline controls. Compared to pmVIC cultures, paVIC cultures had greater total phosphate mineralization, ALPa, calcium content, and apoptosis, under both a baseline control and LPC-treated conditions. Conclusions This study showed that LPC has the capacity to promote pVIC calcification. Also, paVICs have a greater propensity for mineralization than pmVICs. LPC may be a key factor in the transition of the aortic valve from a healthy to diseased state. In addition, there are intrinsic differences that exist between VICs from different valves that may play a key role in heart valve pathology.

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Section: Discussionmentioning

confidence: 99%

Differential Aortic and Mitral Valve Interstitial Cell Mineralization and the Induction of Mineralization by Lysophosphatidylcholine In Vitro

Wiltz

Han

Wilson

et al. 2014

Cardiovasc Eng Tech

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“…This implies that genetic variations in the OPG gene may play a role in the pathophysiology of this disease. Since several currently available drugs have been shown to retard the rate of arterial calcification, e. g. hormone replacement therapy, selective estrogen receptor modulators, statins and calcium channel blockers [45], these findings may be informative for the primary prevention of this disease. Whether early pharmacological intervention, aimed at reducing vessel wall mineralization in this genetic subpopulation, is warranted for the prevention of ICH, remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms at the Osteoprotegerin and Interleukin-6 Genes in Relation to First-Ever Stroke

Strand¹,

Söderström²,

Wiklund³

et al. 2007

Cerebrovasc Dis

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Background: Arterial calcification and osteoporosis often coexist, especially in postmenopausal women. Osteoporosis associates with a substantially increased risk of stroke in elderly women, suggesting that impaired estrogen signaling may link stroke and osteoporosis. Osteoprotegerin (OPG, TNFRSF11B) and interleukin-6 (IL-6, IL6) are putative target genes for estrogen signaling and have been implicated in both cardiovascular diseases and osteoporosis. We hypothesized that specific polymorphisms in these genes may be associated with increased risk of ischemic stroke or intracerebral hemorrhage (ICH). Methods: We performed a population-based prospective nested case-control study, in which the relationships between polymorphisms (OPG-1181G/C, OPG-950T/C and IL6-174G/C) and ischemic stroke and ICH were examined. Definitive first-ever stroke events (n = 388), i.e. ischemic stroke (n = 320), ICH (n = 61) and unspecified stroke (n = 7) cases, and controls without cardiovascular disease (n = 773), matched for age, sex and geographical region were studied. Univariate and multivariate models using conditional logistic regression, which included traditional risk factors, were used to test for association. Results: Carriers of the OPG-1181C/C genotype had a significantly (p = 0.018) increased risk of ICH (OR, 2.69; 95% CI, 1.19–6.12) in the univariate analysis. After adjustments (hypertension, diabetes, BMI and triglycerides), this genotype remained significantly (p = 0.005) associated with ICH (OR, 6.04; 95% CI, 1.71–21.29). By contrast, no correlations were found between this genotype and ischemic stroke, nor between the OPG-950T/C or IL6-174G/C polymorphisms and stroke subtypes. Conclusions: In this population, the OPG-1181C/C genotype associates with first-ever ICH, implying that alterations in OPG-mediated signaling in the vasculature may be involved in the pathophysiology of this disease.

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“…58 Similarly, osteogenic reprogramming is well described in vascular (particularly medial) calcification. 59,60 Bone morphogenetic protein 2 (BMP-2)-dependent signalling has been shown to lead to activation of osteoblast-associated transcription factors and the resultant increased expression of osteogenic proteins. 61–63 Using advanced material-based analytical methods, investigators identified spherical particles containing calcium phosphate mineral in calcified aortic valves and calcific regions of the vessel wall.…”

Section: Pathophysiologymentioning

confidence: 99%

Potential drug targets for calcific aortic valve disease

2014

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Calcific aortic valve disease (CAVD) is a major contributor to cardiovascular morbidity and mortality and, given its association with age, the prevalence of CAVD is expected to continue to rise as global life expectancy increases. No drug strategies currently exist to prevent or treat CAVD. Given that valve replacement is the only available clinical option, patients often cope with a deteriorating quality of life until diminished valve function demands intervention. The recognition that CAVD results from active cellular mechanisms suggests that the underlying pathways might be targeted to treat the condition. However, no such therapeutic strategy has been successfully developed to date. One hope was that drugs already used to treat vascular complications might also improve CAVD outcomes, but the mechanisms of CAVD progression and the desired therapeutic outcomes are often different from those of vascular diseases. We, therefore, discuss the benchmarks that must be met by a CAVD treatment approach, and highlight advances in the understanding of CAVD mechanisms to identify potential novel therapeutic targets.

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Arterial calcification: A review of mechanisms, animal models, and the prospects for therapy

Cited by 200 publications

References 223 publications

Differential Aortic and Mitral Valve Interstitial Cell Mineralization and the Induction of Mineralization by Lysophosphatidylcholine In Vitro

Differential Aortic and Mitral Valve Interstitial Cell Mineralization and the Induction of Mineralization by Lysophosphatidylcholine In Vitro

Polymorphisms at the Osteoprotegerin and Interleukin-6 Genes in Relation to First-Ever Stroke

Potential drug targets for calcific aortic valve disease

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