Inhibition of calcifying nodule formation in cultured porcine aortic valve cells by nitric oxide donors

Kennedy, Jennifer A.; Xiang, Hua; Mishra, Kumaril; Murphy, Geraldine A.; Rosenkranz, A; Horowitz, John D.

doi:10.1016/j.ejphar.2008.11.029

Cited by 73 publications

(80 citation statements)

References 39 publications

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“…Somewhat surprisingly, MnSOD deficiency did not impact aortic valve function compared with wild-type mice in both age groups. We anticipated that losses in mitochondrial antioxidant capacity would negatively impact aortic valve function with aging, due to previous studies suggesting that increases in oxidative stress are strongly associated with calcification in tissue from humans with calcific aortic valve disease (27), and experimental data suggesting that increases in oxidative stress and reductions in nitric oxide bioavailability accelerate cardiovascular cell calcification in vitro (5,22). A possible explanation for the contrast in findings is that the mice used in this study were not exposed to significant exogenous stressors (e.g., high fat diet, hypertensive stress, etc.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional and phenotypic changes in aorta and aortic valve with aging and MnSOD deficiency in mice

Roos

Hagler

Zhang

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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-The purpose of this study was to characterize changes in antioxidant and age-related gene expression in aorta and aortic valve with aging, and test the hypothesis that increased mitochondrial oxidative stress accelerates age-related endothelial and aortic valve dysfunction. Wildtype (MnSOD ϩ/ϩ ) and manganese SOD heterozygous haploinsufficient (MnSOD ϩ/Ϫ ) mice were studied at 3 and 18 mo of age. In aorta from wild-type mice, antioxidant expression was preserved, although there were age-associated increases in Nox2 expression. Haploinsufficiency of MnSOD did not alter antioxidant expression in aorta, but increased expression of Nox2. When compared with that of aorta, age-associated reductions in antioxidant expression were larger in aortic valves from wild-type and MnSOD haploinsufficient mice, although Nox2 expression was unchanged. Similarly, sirtuin expression was relatively well-preserved in aorta from both genotypes, whereas expression of SIRT1, SIRT2, SIRT3, SIRT4, and SIRT6 were significantly reduced in the aortic valve. Expression of p16 ink4a , a marker of cellular senescence, was profoundly increased in both aorta and aortic valve from MnSOD ϩ/ϩ and MnSOD ϩ/Ϫ mice. Functionally, we observed comparable age-associated reductions in endothelial function in aorta from both MnSOD ϩ/ϩ and MnSOD ϩ/Ϫ mice. Interestingly, inhibition of NAD(P)H oxidase with apocynin or gp91ds-tat improved endothelial function in MnSOD ϩ/ϩ mice but significantly impaired endothelial function in MnSOD ϩ/Ϫ mice at both ages. Aortic valve function was not impaired by aging or MnSOD haploinsufficiency. Changes in antioxidant and sirtuin gene expression with aging differ dramatically between aorta and aortic valve. Furthermore, although MnSOD does not result in overt cardiovascular dysfunction with aging, compensatory transcriptional responses to MnSOD deficiency appear to be tissue specific.aging; mitochondrial oxidative stress; endothelial function; aorta; aortic valve INCREASING AGE IS ASSOCIATED with increases in reactive oxygen species (ROS), which is thought to contribute to the development of age-related cardiovascular disease. Previous work in aged humans and animals has shown that NAD(P)H oxidase contributes to age-related endothelial dysfunction and vascular fibrosis and that reducing SOD1 (cytosolic), SOD2 (mitochondrial), or SOD3 (extracellular) worsens endothelial function with aging (3,4,12,13,19,25). Furthermore, we have previously shown that aortic valve calcification is strongly associated with increases in oxidative stress and reductions in antioxidant defense mechanisms in humans (27), and several studies have shown that the balance between oxidative stress and nitric oxide bioavailability is an important determinant of vascular and valvular calcification in vitro (27,39,41). Interestingly, emerging data from in vitro experiments also suggest that, once initiated, ROS production may self-perpetuate (ROS-induced ROS-release), accelerate development of endothelial dysfunction, and accelerate development of age-relate...

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Section: Discussionmentioning

confidence: 99%

Transcriptional and phenotypic changes in aorta and aortic valve with aging and MnSOD deficiency in mice

Roos

Hagler

Zhang

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…Oxidative stress has been shown to participate in the development of CAVD (Miller et al 2008;Kennedy et al 2009;Li and Förstermann 2013) and be associated with local hemodynamic changes (Richards et al 2013). NOS3, commonly known as eNOS, has long been known for its protective effects against aortic valve inflammation and calcification (Clapp et al 2004;Kennedy et al 2009).…”

Section: Modulementioning

confidence: 99%

“…NOS3, commonly known as eNOS, has long been known for its protective effects against aortic valve inflammation and calcification (Clapp et al 2004;Kennedy et al 2009). Low expression of eNOS can reduce the cellular NO level, thus contributing to oxidative stress and facilitating eNOS uncoupling, which will, in turn, increase the generation of reactive oxygen species (ROS) and promote further oxidative damage to the endothelium (Miller et al 2008;Li and Förstermann 2013).…”

Section: Modulementioning

confidence: 99%

Integrated Bioinformatics Analysis Predicts the Key Genes Involved in Aortic Valve Calcification: From Hemodynamic Changes to Extracellular Remodeling

Liu

Luo

Sun

et al. 2017

Tohoku J. Exp. Med.

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In our aging world, increasing numbers of people are suffering from calcific aortic valve disease (CAVD). In this study, we used integrated bioinformatics analysis to predict several key genes that are involved in the initiation and progression of CAVD. Expression profiles of 15 calcific and 14 normal human aortic valve samples were generated from two gene expression datasets (GSE12644 and GSE51472). Dataset GSE26953 from the human aortic valve fibrosa-derived endothelial cells cultured under laminar or oscillatory shear stress was also evaluated. Related R packages were used to process the data. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for functional annotation. Hub genes were identified based on the protein-protein interaction network. CAVD-related gene modules were identified by Weighted Gene Co-expression Network Analysis (WGCNA). The predicted key genes were manually reviewed. In our present work, complex connections among mechano-response, oxidative stress, inflammation and extracellular remodeling pathways in the etiology of CAVD were revealed. The key genes, thus identified, encode a transcription factor KLF2 and phospholipid phosphatase 3 (PLPP3) that are involved in mechanoresponses; eNOS involved in oxidative stress; IL-8 involved in inflammation; and collagen triple helix repeat containing 1 (CTHRC1) and secretogranin II (SCG2) involved in extracellular remodeling. These gene products are predicted to play critical roles in CAVD development and progression. The present study provides valuable information for future research and drug development.

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“…Наводяться експериментальні дані [81] про роль співвідношення L-аргінін/NO в мо-дуляції кальцифікуючого фенотипу інтер-стиціальних клітин АК та ефективність NO-донації в ранніх протективних механіз мах розвитку клапанної і судинної кальцифікації [72,82]. Ефективність модуляції систе-ми L-аргінін-NO як терапевтичної стра-тегії патогенетичного спрямування що до прогресування кардіоваскулярної кальци-фікації при ХХН продемонстровано нами в клінічних умовах [26].…”

Section: сучасні тенденції розвитку науки індуктори та інгібітори каunclassified

Calcification of Heart and Vessels in Chronic Kidney Disease: Problems of Etiology and Pathogenesis

Susla¹,

Gozhenko²,

Bergier³

et al. 2017

Fiziol Zh

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Inhibition of calcifying nodule formation in cultured porcine aortic valve cells by nitric oxide donors

Cited by 73 publications

References 39 publications

Transcriptional and phenotypic changes in aorta and aortic valve with aging and MnSOD deficiency in mice

Transcriptional and phenotypic changes in aorta and aortic valve with aging and MnSOD deficiency in mice

Integrated Bioinformatics Analysis Predicts the Key Genes Involved in Aortic Valve Calcification: From Hemodynamic Changes to Extracellular Remodeling

Calcification of Heart and Vessels in Chronic Kidney Disease: Problems of Etiology and Pathogenesis

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