Receptor activator of nuclear factor κB ligand and osteoprotegerin regulate aortic valve calcification

Kaden, Jens J.

doi:10.1016/j.yjmcc.2003.09.015

Cited by 254 publications

(213 citation statements)

References 29 publications

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“…Proteins involved in regulation of tissue calcification have been detected in calcified valvular tissue, including osteopontin, 13,14 bone morphogenic proteins (BMPs) 2 and 4, 15 and receptor activator of nuclear factor NF-B ligand (RANKL). 65 Osteoprotegrin (OPG), which prevents mineral resorption in bone tissue, is a soluble decoy receptor that resembles RANK and acts as a competitive inhibitor of RANK binding to RANKL. RANK is expressed in normal valve leaflets, but is downregulated in aortic valve lesions.…”

Section: Calcificationmentioning

confidence: 99%

“…RANK is expressed in normal valve leaflets, but is downregulated in aortic valve lesions. 65 The osteoblast-specific transcription factor, Runx2/Cbfa1, has been detected in rabbit models of experimental aortic valve disease, 16,17,27 and osteoblast-like cells have been identified both in a rabbit model 17 and in calcified human valves. 15 Finally, a subset of end-stage human aortic valve lesions contain heterotopic bone, 15 further confirming the dysregulated nature of aortic valvular calcification.…”

Section: Calcificationmentioning

confidence: 99%

“…12 They also contain tenascin C, 66 an extracellular matrix glycoprotein found in developing bones. 66 Recently, groups have isolated a subset of valvular fibroblasts that express osteoblast markers 57,65 and spontaneously form hydroxyapatite-containing calcified nodules in vitro. 57,65 In response to oxidized cholesterol, 57 transforming growth factor (TGF) ␤1, 57 BMP2, 57 and RANKL, 65 these cells increase their expression of osteoblast markers and increase their rate of calcified nodule formation.…”

Section: Calcificationmentioning

confidence: 99%

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Pathogenesis of Calcific Aortic Valve Disease

O’Brien

2006

ATVB

249

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Background-Over the past 10 to 15 years, calcific aortic valve disease, which includes aortic sclerosis and aortic stenosis, has come to be recognized as an active process, based on: (1) epidemiologic studies demonstrating associations of specific risk factors with increased prevalence or rate of progression of aortic valve disease; (2) identification, in valve lesions, of histopathologic features of chronic inflammation, lipoprotein deposition, renin-angiotensin system components, and molecular mediators of calcification; and (3) identification of cell-signaling pathways and genetic factors that may participate in valve disease pathogenesis. These studies will be reviewed and organized into a proposed global hypothesis for the pathogenesis of calcific aortic valve disease. Key Words: aortic valve disease Ⅲ calcification Ⅲ lipoproteins Ⅲ matrix Ⅲ angiotensin II C alcific aortic valve disease is identified by thickening and calcification of the aortic valve leaflets in the absence of rheumatic heart disease. It is divided, on a functional basis, into aortic sclerosis, in which the leaflets do not obstruct left ventricular outflow, and aortic stenosis, in which obstruction to left ventricular outflow is present. Aortic sclerosis is present in more than 25% of patients over age 65 1 and is associated with a 50% increase risk of cardiovascular events. 2 Aortic stenosis is present in 2% to 5% of very elderly patients, 1,3 is the second most common indication for cardiac surgery, 4 and carries an 80% 5-year risk of progression to heart failure, valve replacement, or death. 5 Though the disease is associated with substantial clinical consequences, there currently is no effective therapy for the disease other than surgical aortic valve replacement.The lack of medical therapies for calcific aortic valve disease can be traced to at least two important issues, one intellectual, the other practical. The first was the long-held notion that calcific aortic valve disease was a "degenerative," and therefore unmodifiable, condition. 6 However, more recent studies have demonstrated convincingly that calcific aortic valve lesions have many features characteristic of an active pathobiological process, including chronic inflammation, 7-9 lipoprotein deposition, 10 -12 active calcification, [13][14][15][16][17][18] and renin-angiotensin system activation. 19,20 These features are present in both trileaflet and bileaflet aortic valve lesions. 21 Also, an emerging body of literature is investigating how genetic factors might influence disease development. [22][23][24][25] The second issue is that, for many years, there were no animal models that faithfully replicated the key histological features of the disease. Recently, rabbit models been developed, 16,26,27 with that of Rajamannan and colleagues already providing a number of novel insights. 16 -18,28,29 In particular, these models have implicated the Wnt 18 and Runx2/ Cbfa1 16,17,27 signaling pathways in disease pathogenesis. Only very recently has a purported mouse model of calcif...

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Section: Calcificationmentioning

confidence: 99%

Section: Calcificationmentioning

confidence: 99%

Section: Calcificationmentioning

confidence: 99%

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Pathogenesis of Calcific Aortic Valve Disease

O’Brien

2006

ATVB

249

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“…RANKL-лиганд для активации рецептора NF-κB -RANK на поверхно-стях остеокластов. RANKL стимуляция рецептора ведет одновременно к активации остеокластогенеза, а также к стимуляции экспрессии Runx2 у больных с АС [28]. Остеопротегерин является ингибитором RANK/RANKL пути, а TNF-α -наоборот, его акти-ватором.…”

Section: Wnt/ β -катениновый путьunclassified

“…Остеопротегерин является ингибитором RANK/RANKL пути, а TNF-α -наоборот, его акти-ватором. Так, при АС был выявлен пониженный уро-вень остеопротегерина наряду с повышенной экс-прессией RANKL [28]. RANK/RANKL путь также непосред ственно способствует накоплению кальция в МКМ.…”

Section: Wnt/ β -катениновый путьunclassified