Increased dietary intake of vitamin A promotes aortic valve calcification in vivo.
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ABSTRACT:
SUBMITTER: Huk DJ
PROVIDER: S-EPMC3557503 | biostudies-literature | 2013 Feb
REPOSITORIES: biostudies-literature
Publications
Increased dietary intake of vitamin A promotes aortic valve calcification in vivo.
Huk Danielle J DJ Hammond Harriet L HL Kegechika Hiroyuki H Lincoln Joy J
Arteriosclerosis, thrombosis, and vascular biology 20121129 2
<h4>Objective</h4>Calcific aortic valve disease (CAVD) is a major public health problem with no effective treatment available other than surgery. We previously showed that mature heart valves calcify in response to retinoic acid (RA) treatment through downregulation of the SRY transcription factor Sox9. In this study, we investigated the effects of excess vitamin A and its metabolite RA on heart valve structure and function in vivo and examined the molecular mechanisms of RA signaling during the ...[more]
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Project description:Calcific aortic valve disease (CAVD) is a significant cause of morbidity and mortality, which affects ?1% of the US population and is characterized by calcific nodule formation and stenosis of the valve. Klotho-deficient mice were used to study the molecular mechanisms of CAVD as they develop robust aortic valve (AoV) calcification. Through microarray analysis of AoV tissues from klotho-deficient and wild-type mice, increased expression of the gene encoding cyclooxygenase 2 (COX2; Ptgs2) was found. COX2 activity contributes to bone differentiation and homeostasis, thus the contribution of COX2 activity to AoV calcification was assessed.In klotho-deficient mice, COX2 expression is increased throughout regions of valve calcification and is induced in the valvular interstitial cells before calcification formation. Similarly, COX2 expression is increased in human diseased AoVs. Treatment of cultured porcine aortic valvular interstitial cells with osteogenic media induces bone marker gene expression and calcification in vitro, which is blocked by inhibition of COX2 activity. In vivo, genetic loss of function of COX2 cyclooxygenase activity partially rescues AoV calcification in klotho-deficient mice. Moreover, pharmacological inhibition of COX2 activity in klotho-deficient mice via celecoxib-containing diet reduces AoV calcification and blocks osteogenic gene expression.COX2 expression is upregulated in CAVD, and its activity contributes to osteogenic gene induction and valve calcification in vitro and in vivo.
| S-EPMC4979542 | biostudies-literature
Project description:BackgroundIn animal studies, zinc supplementation inhibited phosphate-induced arterial calcification. We tested the hypothesis that higher intake of dietary zinc was associated with lower abdominal aortic calcification (AAC) among adults in the USA. We also explored the associations of AAC with supplemental zinc intake, total zinc intake and serum zinc level.MethodsWe performed cross-sectional analyses of 2535 participants from the National Health and Nutrition Examination Survey 2013-14. Dietary and supplemental zinc intakes were obtained from two 24-h dietary recall interviews. Total zinc intake was the sum of dietary and supplemental zinc. AAC was measured using dual-energy X-ray absorptiometry in adults ≥40 years of age and quantified using the Kauppila score system. AAC scores were categorized into three groups: no AAC (AAC = 0, reference group), mild-moderate (AAC >0-≤6) and severe AAC (AAC >6).ResultsDietary zinc intake (mean ± SE) was 10.5 ± 0.1 mg/day; 28% had AAC (20% mild-moderate and 8% severe), 17% had diabetes mellitus and 51% had hypertension. Higher intake of dietary zinc was associated with lower odds of having severe AAC. Per 1 mg/day higher intake of dietary zinc, the odds of having severe AAC were 8% lower [adjusted odds ratio 0.92 (95% confidence interval 0.86-0.98), P = 0.01] compared with those without AAC, after adjusting for demographics, comorbidities and laboratory measurements. Supplemental zinc intake, total zinc intake and serum zinc level were not associated with AAC.ConclusionsHigher intake of dietary zinc was independently associated with lower odds of having severe AAC among noninstitutionalized US adults.
| S-EPMC7417001 | biostudies-literature
Project description:RATIONALE:Calcification of heart valve structures is the most common form of valvular disease and is characterized by the appearance of bone-like phenotypes within affected structures. Despite the clinical significance, the underlying etiology of disease onset and progression is largely unknown and valve replacement remains the most effective treatment. The SRY-related transcription factor Sox9 is expressed in developing and mature heart valves, and its function is required for expression of cartilage-associated proteins, similar to its role in chondrogenesis. In addition to cartilage-associated defects, mice with reduced sox9 function develop skeletal bone prematurely; however, the ability of sox9 deficiency to promote ectopic osteogenic phenotypes in heart valves has not been examined. OBJECTIVE:This study aims to determine the role of Sox9 in maintaining connective tissue homeostasis in mature heart valves using in vivo and in vitro approaches. METHODS AND RESULTS:Using histological and molecular analyses, we report that, from 3 months of age, Sox9(fl/+);Col2a1-cre mice develop calcific lesions in heart valve leaflets associated with increased expression of bone-related genes and activation of inflammation and matrix remodeling processes. Consistently, ectopic calcification is also observed following direct knockdown of Sox9 in heart valves in vitro. Furthermore, we show that retinoic acid treatment in mature heart valves is sufficient to promote calcific processes in vitro, which can be attenuated by Sox9 overexpression. CONCLUSIONS:This study provides insight into the molecular mechanisms of heart valve calcification and identifies reduced Sox9 function as a potential genetic basis for calcific valvular disease.
| S-EPMC2863131 | biostudies-literature
Project description:BackgroundCardiovascular disease (CVD) is the leading cause of mortality, and vascular calcification has been highly correlated with CVD events. Abdominal aortic calcification (AAC) has been shown to predict subclinical CVD and incident CVD events. However, the relationship between vitamin C and abdominal aortic calcification remains unclear.ObjectiveTo investigate the relationship of dietary vitamin C with AAC among the adult population in the US.MethodsThe National Health and Nutrition Examination Survey (NHANES) 2013-2014 provided the data for the cross-sectional study. 2297 subjects (1089 males) were included in the study. Two scoring systems, AAC 24-point scale (Kauppila) and AAC 8-point scale (Schousboe), were used for the measurement of AAC score. Dietary vitamin C intake was calculated as the average of two rounds of 24-h interview recall data and classified in tertiles for analysis. We applied weighted multiple regression analyses to assess the relationship of dietary vitamin C with AAC score and the risk of having AAC. To ensure the robustness of the findings, subgroup and sensitivity analyses were performed. Additionally, smooth curve fittings, using generalized additive models (GAM) were employed to visualize potential nonlinear relationships. Furthermore, an exploratory analysis on the relationship of vitamin C supplements with AAC was also conducted.ResultsThe results showed that higher dietary vitamin C intake was related to a reduction in AAC score (AAC-24: β = -0.338, 95% confidence interval [CI] -0.565, -0.111, P = 0.004; AAC-8: β = -0.132, 95%CI -0.217, -0.047, P = 0.002), and lower risk of AAC (odds ratio [OR] = 0.807, 95%CI 0.659, 0.989, P = 0.038). However, the relationship of vitamin C supplements with AAC was not identified.ConclusionsThe study revealed that higher intake of dietary vitamin C rather than vitamin C supplements was related to reduced AAC score and lower risk of AAC, indicating that diets rich in vitamin C are recommended due to its potential benefits for protecting against vascular calcification and CVD among the adult population in the US.
| S-EPMC10647183 | biostudies-literature
Project description:miR-214 has been recently found to be significantly downregulated in calcified human aortic valves (AVs). ER stress, especially the ATF4-mediated pathway, has also been shown to be significantly upregulated in calcific AV disease. Since elevated cyclic stretch is one of the major mechanical stimuli for AV calcification and ATF4 is a validated target of miR-214, we investigated the effect of cyclic stretch on miR-214 expression as well as those of ATF4 and two downstream genes (CHOP and BCL2L1). Porcine aortic valve (PAV) leaflets were cyclically stretched at 15% for 48 h in regular medium and for 1 week in osteogenic medium to simulate the early remodeling and late calcification stages of stretch-induced AV disease, respectively. For both stages, 10% cyclic stretch served as the physiological counterpart. RT-qPCR revealed that miR-214 expression was significantly downregulated during the late calcification stage, whereas the mRNA expression of ATF4 and BCL2L1 was upregulated and downregulated, respectively, during both early remodeling and late calcification stages. When PAV leaflets were statically transfected with miR-214 mimic in osteogenic medium for 2 weeks, calcification was significantly reduced compared to the control mimic case. This implies that miR-214 may have a protective role in stretch-induced calcific AV disease.
| S-EPMC6416061 | biostudies-literature
Project description:AimsThere is evidence to suggest that the subtype of aortic stenosis (AS), the degree of myocardial fibrosis (MF), and level of aortic valve calcification (AVC) are associated with adverse cardiac outcome in AS. Because little is known about their respective contribution, we sought to investigate their relative importance and interplay as well as their association with adverse cardiac events following transcatheter aortic valve replacement (TAVR).Methods and resultsOne hundred consecutive patients with severe AS and indication for TAVR were prospectively enrolled between January 2017 and October 2018. Patients underwent transthoracic echocardiography, multidetector computed tomography, and left ventricular endomyocardial biopsies at the time of TAVR. The final study cohort consisted of 92 patients with a completed study protocol, 39 (42.4%) of whom showed a normal ejection fraction (EF) high-gradient (NEFHG) AS, 13 (14.1%) a low EF high-gradient (LEFHG) AS, 25 (27.2%) a low EF low-gradient (LEFLG) AS, and 15 (16.3%) a paradoxical low-flow, low-gradient (PLFLG) AS. The high-gradient phenotypes (NEFHG and LEFHG) showed the largest amount of AVC (807 ± 421 and 813 ± 281 mm3 , respectively) as compared with the low-gradient phenotypes (LEFLG and PLFLG; 503 ± 326 and 555 ± 594 mm3 , respectively, P < 0.05). Conversely, MF was most prevalent in low-output phenotypes (LEFLG > LEFHG > PLFLG > NEFHG, P < 0.05). This was paralleled by a greater cardiovascular (CV) mortality within 600 days after TAVR (LEFLG 28% > PLFLG 26.7% > LEFHG 15.4% > NEFHG 2.5%; P = 0.023). In patients with a high MF burden, a higher AVC was associated with a lower mortality following TAVR (P = 0.045, hazard ratio 0.261, 95% confidence interval 0.07-0.97).ConclusionsMF is associated with adverse CV outcome following TAVR, which is most prevalent in low EF situations. In the presence of large MF burden, patients with large AVC have better outcome following TAVR. Conversely, worse outcome in large MF and relatively little AVC may be explained by a relative prominence of an underlying cardiomyopathy. The better survival rates in large AVC patients following TAVR indicate TAVR induced relief of severe AS-associated pressure overload with subsequently improved outcome.
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Project description:BackgroundCellular communication network factor 3 (CCN3) has been implicated in the regulation of osteoblast differentiation. However, it is not known if CCN3 can regulate valvular calcification. While macrophages have been shown to regulate valvular calcification, the molecular and cellular mechanisms of this process remain poorly understood. In the present study, we investigated the role of macrophage-derived CCN3 in the progression of calcific aortic valve disease.MethodsMyeloid-specific knockout of CCN3 (Mye-CCN3-KO) and control mice were subjected to a single tail intravenous injection of AAV encoding mutant mPCSK9 (rAAV8/D377Y-mPCSK9) to induce hyperlipidemia. AAV-injected mice were then fed a high fat diet for 40 weeks. At the conclusion of high fat diet feeding, tissues were harvested and subjected to histologic and pathologic analyses. In vitro, bone marrow-derived macrophages (BMDM) were obtained from Mye-CCN3-KO and control mice and the expression of bone morphogenic protein signaling related gene were verified via quantitative real-time PCR and Western blotting. The BMDM conditioned medium was cocultured with human valvular intersititial cells which was artificially induced calcification to test the effect of the conditioned medium via Western blotting and Alizarin red staining.ResultsEchocardiography revealed that both male and female Mye-CCN3-KO mice displayed compromised aortic valvular function accompanied by exacerbated valve thickness and cardiac dysfunction. Histologically, Alizarin-Red staining revealed a marked increase in aortic valve calcification in Mye-CCN3-KO mice when compared to the controls. In vitro, CCN3 deficiency augmented BMP2 production and secretion from bone marrow-derived macrophages. In addition, human valvular interstitial cells cultured with conditioned media from CCN3-deficient BMDMs resulted in exaggerated pro-calcifying gene expression and the consequent calcification.ConclusionOur data uncovered a novel role of myeloid CCN3 in the regulation of aortic valve calcification. Modulation of BMP2 production and secretion in macrophages might serve as a key mechanism for macrophage-derived CCN3's anti-calcification function in the development of CAVD. Video Abstract.
| S-EPMC9854076 | biostudies-literature
Project description:One key risk factor of aortic valve stenosis in clinical practice is bicuspid aortic valve (BAV). Increasing evidence indicates that numerous microRNAs (miRs/miRNAs) are involved in BAV calcification via their target genes. miR‑330‑3p was found to be involved in the deterioration of BAV calcification by miR profiling in human calcified BAV and tricuspid aortic valve (TAV) tissues in the present study and the underlying mechanism was investigated. RNA sequencing was performed on four BAV and four TAV tissues from patients with aortic stenosis before these leaflets were examined for the expression levels of miR‑330‑3p and CREB‑binding protein (CREBBP) by reverse transcription‑PCR. The alteration of functional factors associated with calcification was also assessed by Western blotting and immunohistochemistry in human aortic tissue samples. The putative target of miR‑330‑3p was detected by dual‑luciferase assay in 293 cells. Furthermore, the influence of miR‑330‑3p expression on osteogenic progression was explored in cultured porcine valve interstitial cells (VICs). Rescue experiments of CRBBP were performed to confirm the influence of the miR‑330‑3p‑CREBBP pathway in the calcification progress in porcine VICs. RNA sequencing indicated distinct expression of miR‑330‑3p in human BAV tissues compared with TAV, which was then confirmed by PCR. CREBBP expression levels in human BAV and TAV leaflets also demonstrated the opposite alterations. This negative correlation was then confirmed in cultured porcine VICs. Under an osteogenic environment, cellular calcification was promoted in miR‑330‑3p‑overexpressed porcine VICs expressing higher bone morphogenetic protein 2, Runt‑related transcription factor 2, matrix metalloproteinase (MMP)‑2, MMP‑9 and collagen I compared with controls. Rescue experiments further confirmed that miR‑330‑3p played its role via targeting CREBBP in porcine VICs. Collectively, miR‑330‑3p was upregulated in calcified BAV compared with TAV. The upregulation of miR‑330‑3p promotes the calcification progress partially via targeting CREBBP.
| S-EPMC7411470 | biostudies-literature
Project description:Background:Atrioventricular block requiring permanent pacemaker (PPM) implantation is a common complication of transcatheter aortic valve replacement (TAVR). The mechanism of atrioventricular (AV) block during TAVR is not fully understood, but it may be due to the mechanical stress of TAVR deployment, resulting in possible injury to the nearby compact AV node. Aortic valve calcification (AVC) may worsen this condition and has been associated with an increased risk for post-TAVR PPM implantation. We performed a retrospective analysis to determine if AVC is predictive for long-term right ventricular (RV) pacing in post-TAVR pacemaker patients at 30 days. Methods:A total of 262 consecutive patients who underwent TAVR with a balloon-expandable valve were analyzed. AVC data were derived from contrast-enhanced computed tomography and characterized by leaflet sector and region. Results:A total of 25 patients (11.1%) required post-TAVR PPM implantation. Seventeen patients did not require RV pacing at 30 days. Nine of these 17 patients had no RV pacing requirement within 10 days. The presence of intra-procedural heart block (P = 0.004) was the only significant difference between patients who did not require PPM and those who required PPM but they were not RV pacing-dependent at 30 days. Non-coronary cusp (NCC) calcium volume was significantly higher in patients who were pacemaker-dependent at 30 days (P = 0.01) and a calcium volume of > 239.2 mm3 in the NCC was strongly predictive of pacemaker dependence at 30 days (area under the curve (AUC) = 0.813). Pre-existing right bundle branch block (RBBB) (odds ratio (OR) 105.4, P = 0.004), bifascicular block (OR 12.5, P = 0.02), QRS duration (OR 70.43, P = 0.007) and intra-procedural complete heart block (OR 12.83, P = 0.03) were also predictive of pacemaker dependence at 30 days. Conclusions:In patients who required PPM after TAVR, quantification of AVC by non-coronary leaflet calcium volume was found to be a novel predictor for RV pacing dependence at 30 days. The association of NCC calcification and PPM dependence may be related to the proximity of the conduction bundle to the non-coronary leaflet. Further studies are necessary to improve risk prediction for long-term RV pacing requirements following TAVR.
| S-EPMC7239596 | biostudies-literature
Project description:BackgroundMenaquinone-7 (MK-7), also known as vitamin K2, is a cofactor for the carboxylation of proteins involved in the inhibition of arterial calcification and has been suggested to reduce the progression rate of aortic valve calcification (AVC) in patients with aortic stenosis.MethodsIn a randomized, double-blind, multicenter trial, men from the community with an AVC score >300 arbitrary units (AU) on cardiac noncontrast computer tomography were randomized to daily treatment with tablet 720 µg MK-7 plus 25 µg vitamin D or matching placebo for 24 months. The primary outcome was the change in AVC score. Selected secondary outcomes included change in aortic valve area and peak aortic jet velocity on echocardiography, heart valve surgery, change in aortic and coronary artery calcification, and change in dp-ucMGP (dephosphorylated-undercarboxylated matrix Gla-protein). Safety outcomes included all-cause death and cardiovascular events.ResultsFrom February 1, 2018, to March 21, 2019, 365 men were randomized. Mean age was 71.0 (±4.4) years. The mean (95% CI) increase in AVC score was 275 AU (95% CI, 225-326 AU) and 292 AU (95% CI, 246-338 AU) in the intervention and placebo groups, respectively. The mean difference on AVC progression was 17 AU (95% CI, -86 to 53 AU; P=0.64). The mean change in aortic valve area was 0.02 cm2 (95% CI, -0.09 to 0.12 cm2; P=0.78) and in peak aortic jet velocity was 0.04 m/s (95% CI, -0.11 to 0.02 m/s; P=0.21). The progression in aortic and coronary artery calcification score was not significantly different between patients treated with MK-7 plus vitamin D and patients receiving placebo. There was no difference in the rate of heart valve surgery (1 versus 2 patients; P=0.99), all-cause death (1 versus 4 patients; P=0.37), or cardiovascular events (10 versus 10 patients; P=0.99). Compared with patients in the placebo arm, a significant reduction in dp-ucMGP was observed with MK-7 plus vitamin D (-212 pmol/L versus 45 pmol/L; P<0.001).ConclusionsIn elderly men with an AVC score >300 AU, 2 years MK-7 plus vitamin D supplementation did not influence AVC progression.RegistrationURL: https://www.Clinicaltrialsgov; Unique identifier: NCT03243890.
| S-EPMC9047644 | biostudies-literature