Uraemic hyperparathyroidism causes a reversible inflammatory process of aortic valve calcification in rats

Shuvy, Mony; Abedat, Suzan; Beeri, Rоnen; Danenberg, Haim; Planer, David; Ben‐Dov, Iddo Z.; Meir, Karen; Sosna, Jacob; Lotan, Chaim

doi:10.1093/cvr/cvn088

Cited by 38 publications

(30 citation statements)

References 36 publications

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“…This unique model is based on the development of transient uremia-induced secondary hyperparathyroidism and represents the metabolic and hormonal changes occurring in calcification secondary to RF. Interestingly, AVC almost completely regressed after RF resolution and normalization of metabolic abnormalities, implying, for the first time, that AVC might be a reversible process (31). Similar results have been shown in a mouse model using a hypercholesterolemic animal model of aortic valve disease (21).…”

supporting

confidence: 77%

“…The decline in apoptosis might be explained by a reduction in the inflammatory process bringing up a new equilibrium in cell apoptosis and renewal. The reversibility of calcification was recently confirmed in an additional model of AVC based on high LDL-cholesterol levels (21,31). The authors of that study demonstrated that rapid normalization of cholesterol levels in mice resulted in a regression of AVC.…”

Section: Apoptosis and Related Pathways In Avcmentioning

confidence: 83%

“…We developed a RF-induced animal model for AVC based on feeding rats with a high-adenine (0.75%) and high-phosphate (1.5%) diet (31). Adenine causes crystal precipitates in renal tubules and forms 2,8-dihydroxyadenine aggregates.…”

Section: Animal Modelmentioning

confidence: 99%

“…Previously, we (31) demonstrated that an adenine-and phosphate-enriched diet can induce AVC in rats. This unique model is based on the development of transient uremia-induced secondary hyperparathyroidism and represents the metabolic and hormonal changes occurring in calcification secondary to RF.…”

mentioning

confidence: 95%

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Raloxifene attenuates Gas6 and apoptosis in experimental aortic valve disease in renal failure

Shuvy

Abedat

Beeri

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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failure is associated with aortic valve calcification. Using our rat model of uremiainduced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in that disease. We also explored the effects of raloxifene, an estrogen receptor modulator, on valvular calcification. Gene array analysis was performed in aortic valves obtained from three groups of rats (n ϭ 7 rats/group): calcified valves obtained from rats fed with uremic diet, valves after calcification resolution following diet cessation, and control. In addition, four groups of rats (n ϭ 10 rats/group) were used to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet that also received daily raloxifene. Evaluation included imaging, histology, and antigen expression analysis. Gene array results showed that the majority of the altered expressed genes were in diet group valves. Most apoptosisrelated genes were changed in a proapoptotic direction in calcified valves. Apoptosis and decreases in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of survival pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. In conclusion, downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure.growth arrest-specific 6; uremia CARDIOVASCULAR CALCIFICATION is one of the highest causes of morbidities and mortalities in patients with end-stage renal disease. These patients develop aortic valve calcification (AVC) and coronary calcification at an accelerated rate. Associated with this cardiovascular calcification are increased rates of myocardial infarctions and valvular heart disease. The pathogenesis of AVC in renal failure (RF) is not fully elucidated. It has been suggested that the process involves active osteoblast transformation of valve tissue, which results in increased formation of bone matrix (4, 25). Most of the data regarding the pathogenesis of AVC were obtained from animal models based on various components of the metabolic syndrome, emphasizing the role of atherogenesis in AVC (26, 37). In patients with RF, AVC and aortic stenosis are common and progress especially rapidly (18). The prevalence and extent of AVC in this population is poorly explained by traditional cardiovascular risk factors; abnormalities of mineral metabolism are likely to contribute to its development and progression. Current models of RF and accelerated calcification have demonstrated that calcium phosphate metabolism is critical for disease development (13), and inhibitors of calcification (fetuin A) are important in its prevention...

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supporting

confidence: 77%

Section: Apoptosis and Related Pathways In Avcmentioning

confidence: 83%

Section: Animal Modelmentioning

confidence: 99%

mentioning

confidence: 95%

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Raloxifene attenuates Gas6 and apoptosis in experimental aortic valve disease in renal failure

Shuvy

Abedat

Beeri

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…35 In contrast, reversal of aortic valve calcification in uremic rats was shown after removal of adenine and supplemental phosphate from the diet. 36 The mechanism of the calcium resorption was not investigated.…”

Section: Discussionmentioning

confidence: 99%

Persistence of Vascular Calcification after Reversal of Uremia

Lomashvili

Manning

Weitzmann

et al. 2017

The American Journal of Pathology

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The extent to which vascular calcification is reversible and the possible mechanisms are unclear. To address this, calcified aortas from uremic mice were transplanted orthotopically into normal mice, and the calcium content, histology, and minerals of the allografts were compared with the nontransplanted donor aorta. Calcium content decreased immediately after transplantation but remained constant thereafter, with 68% AE 12% remaining after 34 weeks. X-ray diffraction showed the presence of apatite in both donor aortas and allografts. Osteoclasts were absent in the allografts and there was no expression of the macrophage marker CD11b, the osteoclast marker tartrate-resistant acid phosphatase, or carbonic anhydrase II. The initial loss of calcium was less in heavily calcified aortas and was associated with an increase in the Ca/P ratio from 1.49 to 1.63, consistent with a loss of nonapatitic calcium. The results indicate that vascular calcification persists after reversal of uremia, because of a lack of active resorption of apatite. This failure to resorb established calcifications may contribute to the severity of vascular calcification and suggests that therapy should be aimed at prevention.

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A novel mouse model of calcific aortic valve stenosis

Qian,

Wang,

et al. 2024

Anim Models and Exp Med

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BackgroundCalcific aortic valve stenosis (CAVS) is one of the most challenging heart diseases in clinical with rapidly increasing prevalence. However, study of the mechanism and treatment of CAVS is hampered by the lack of suitable, robust and efficient models that develop hemodynamically significant stenosis and typical calcium deposition. Here, we aim to establish a mouse model to mimic the development and features of CAVS.MethodsThe model was established via aortic valve wire injury (AVWI) combined with vitamin D subcutaneous injected in wild type C57/BL6 mice. Serial transthoracic echocardiography was applied to evaluate aortic jet peak velocity and mean gradient. Histopathological specimens were collected and examined in respect of valve thickening, calcium deposition, collagen accumulation, osteogenic differentiation and inflammation.ResultsSerial transthoracic echocardiography revealed that aortic jet peak velocity and mean gradient increased from 7 days post model establishment in a time dependent manner and tended to be stable at 28 days. Compared with the sham group, simple AVWI or the vitamin D group, the hybrid model group showed typical pathological features of CAVS, including hemodynamic alterations, increased aortic valve thickening, calcium deposition, collagen accumulation at 28 days. In addition, osteogenic differentiation, fibrosis and inflammation, which play critical roles in the development of CAVS, were observed in the hybrid model.ConclusionsWe established a novel mouse model of CAVS that could be induced efficiently, robustly and economically, and without genetic intervention. It provides a fast track to explore the underlying mechanisms of CAVS and to identify more effective pharmacological targets.

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Uraemic hyperparathyroidism causes a reversible inflammatory process of aortic valve calcification in rats

Cited by 38 publications

References 36 publications

Raloxifene attenuates Gas6 and apoptosis in experimental aortic valve disease in renal failure

Raloxifene attenuates Gas6 and apoptosis in experimental aortic valve disease in renal failure

Persistence of Vascular Calcification after Reversal of Uremia

A novel mouse model of calcific aortic valve stenosis

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