Aortic valvular interstitial cells apoptosis and calcification are mediated by TNF-related apoptosis-inducing ligand

Galeone, Antonella; Brunetti, Giacomina; Oranger, Angela; Greco, Giovanni; Benedetto, Adriana Di; Mori, Giorgio; Colucci, Silvia; Zallone, Alberta; Paparella, Domenico; Grano, Maria

doi:10.1016/j.ijcard.2013.09.012

Cited by 77 publications

(65 citation statements)

References 42 publications

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“…15,28,29 Recently, Runx2 has been reported to be closely associated with the osteoblast differentiation of VICs in aortic valve calcification. 30,31 Moreover, reactive oxygen species induces the expression of Runx2 through AKT signaling pathway, leading to activation of VICs toward an osteogenic-like phenotype. 32 Conversely, twist-related protein 1 negatively regulates osteoblastic transdifferentiation of human VICs by directly inhibiting Runx2.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-204 Targets Runx2 to Attenuate BMP-2-induced Osteoblast Differentiation of Human Aortic Valve Interstitial Cells

Wang

Chen

Deng

et al. 2015

Journal of Cardiovascular Pharmacology

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Osteoblast differentiation of valve interstitial cells (VICs) is a key step in valve calcification, but the molecular mechanisms involved are not fully understood. In this study, we aimed to investigate whether microRNA (miR)-204-regulated VICs differentiation through modulation of runt-related transcription factor 2 (Runx2), a key transcription factor for osteogenesis. Our data demonstrated that miR-204 was markedly downregulated in both human calcified aortic valves and bone morphogenetic protein (BMP)-2-stimulated aortic VICs. In vitro experiments showed that miR-204 acted as a negative regulator of osteogenic differentiation by repressing Runx2 and thereby inhibiting expression of osteoblast-related genes, including alkaline phosphatase and osteocalcin, which were all induced by BMP-2. Luciferase reporter assays validated Runx2 as the direct target of miR-204. Furthermore, increased alkaline phosphatase activity and osteocalcin expression after miR-204 inhibition were abolished by small interfering RNA-mediated silencing of Runx2. Overall, these data suggested miR-204 as a possible molecular switch inhibiting osteoblastic transdifferentiation of human aortic VICs and targeting miR-204 may have therapeutic potential for human aortic valve calcification.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-204 Targets Runx2 to Attenuate BMP-2-induced Osteoblast Differentiation of Human Aortic Valve Interstitial Cells

Wang

Chen

Deng

et al. 2015

Journal of Cardiovascular Pharmacology

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“…TNFSF10 binding to its receptors will trigger the activation of MAPK8/JNK, caspase 8, and caspase 3. TRAIL mediating calcification of aortic valve interstitial cells via the apoptosis mechanism has been reported [48]. FADD is an adaptor molecule and mediates cell apoptotic signal.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling of Biological Pathway Alterations by Radiation Exposure

Lee

Weng

Hsu

et al. 2014

BioMed Research International

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Though damage caused by radiation has been the focus of rigorous research, the mechanisms through which radiation exerts harmful effects on cells are complex and not well-understood. In particular, the influence of low dose radiation exposure on the regulation of genes and pathways remains unclear. In an attempt to investigate the molecular alterations induced by varying doses of radiation, a genome-wide expression analysis was conducted. Peripheral blood mononuclear cells were collected from five participants and each sample was subjected to 0.5 Gy, 1 Gy, 2.5 Gy, and 5 Gy of cobalt 60 radiation, followed by array-based expression profiling. Gene set enrichment analysis indicated that the immune system and cancer development pathways appeared to be the major affected targets by radiation exposure. Therefore, 1 Gy radioactive exposure seemed to be a critical threshold dosage. In fact, after 1 Gy radiation exposure, expression levels of several genes including FADD, TNFRSF10B, TNFRSF8, TNFRSF10A, TNFSF10, TNFSF8, CASP1, and CASP4 that are associated with carcinogenesis and metabolic disorders showed significant alterations. Our results suggest that exposure to low-dose radiation may elicit changes in metabolic and immune pathways, potentially increasing the risk of immune dysfunctions and metabolic disorders.

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“…However, double knockout IL-1rn −/− Tnf −/− mice are protected and do not develop a thickening of the aortic valve, suggesting that TNFα plays important part in promoting the remodelling of the aortic valve. In humans, the expression of TNF ligand superfamily member 10 (also called TNF-related apoptosis inducing ligand(TRAIL)), a member of the TNF-related cytokines, is increased in calcific AS valves and promotes the mineralization of VIC cultures through the death receptor 4 80 .…”

Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Calcific aortic stenosis

Lindman

Clavel

Mathieu

et al. 2016

Nat Rev Dis Primers

613

525

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Calcific aortic stenosis (AS), the most prevalent heart valve disorder in developed countries,, is characterized by progressive fibro-calcific remodelling and thickening of the aortic valve leaflets that evolve over years to cause severe obstruction to cardiac outflow. In developed countries, AS is the second-most frequent cardiovascular disease after coronary artery disease and systemic arterial hypertension with a prevalence of 0.4% in the general population and 1.7% in the population >65 years old. Congenital abnormality (bicuspid valve) and older age are powerful risk factors for calcific AS. Metabolic syndrome and an elevated plasma level of lipoprotein(a) have also been associated with increased risk of calcific AS. The pathobiology of calcific AS is complex and involves genetic factors, lipoprotein deposition and oxidation, chronic inflammation, osteoblastic transition of cardiac valve interstitial cells and active leaflet calcification Although no pharmacotherapy has proven to be effective in reducing the progression of AS, promising therapeutic targets include lipoprotein(a), the renin-angiotensin system, tumor necrosis factor ligand superfamily member 11 (also called receptor activator of NF-κB ligand (RANKL)) and ectonucleotidases. Currently, aortic valve replacement (AVR) remains the only effective treatment for severe AS. The diagnosis and staging of AS are based on the assessment of stenosis severity and left ventricular systolic function by Doppler echocardiography and the presence of symptoms. The introduction of transcatheter AVR in the past decade has been a transformative innovation for patients at high or extreme-high risk for surgical AVR and this new technology might extend to lower-risk patients in the near future.

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Aortic valvular interstitial cells apoptosis and calcification are mediated by TNF-related apoptosis-inducing ligand

Cited by 77 publications

References 42 publications

MicroRNA-204 Targets Runx2 to Attenuate BMP-2-induced Osteoblast Differentiation of Human Aortic Valve Interstitial Cells

MicroRNA-204 Targets Runx2 to Attenuate BMP-2-induced Osteoblast Differentiation of Human Aortic Valve Interstitial Cells

Gene Expression Profiling of Biological Pathway Alterations by Radiation Exposure

Calcific aortic stenosis

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