Age-Associated Aortic Stenosis in Apolipoprotein E-Deficient Mice

Tanaka, Kimie; Sata, Masataka; Fukuda, Daiju; Suematsu, Yoshihiro; Motomura, Noboru; Takamoto, Shinichi; Hirata, Yasunobu; Nagai, Ryozo

doi:10.1016/j.jacc.2005.03.058

Cited by 128 publications

(94 citation statements)

References 38 publications

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“…CAS shares some risk factors with atherosclerosis and apolipoprotein E knockout mice develop CAS (2,12,13). However, as emphasized by Otto et al (14), CAS and atherosclerosis are not synonymous, given that only half of the patients with CAS have concomitant coronary artery disease, whereas the large majority of those with atherosclerosis do not develop CAS (12).…”

Section: Alcific Aortic Stenosis (Cas)mentioning

confidence: 99%

The Lymphocytic Infiltration in Calcific Aortic Stenosis Predominantly Consists of Clonally Expanded T Cells

Wu¹,

Maurer²,

Friedman³

et al. 2007

The Journal of Immunology

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Valve lesions in degenerative calcific aortic stenosis (CAS), a disorder affecting 3% of those older than 75 years, are infiltrated by T lymphocytes. We sought to determine whether the ␣␤ TCR repertoire of these valve-infiltrating lymphocytes exhibited features either of a polyclonal nonselective response to inflammation or contained expanded clones suggesting a more specific immune process. TCR ␤-chain CDR3-length distribution analysis using PCR primers specific for 23 V␤ families performed in eight individuals with CAS affecting tri-or bileaflet aortic valves revealed considerable oligoclonal T cell expansion. In five cases, ␤-chain nucleotide sequencing in five selected V␤ families showed that an average of 92% of the valve-infiltrating T cell repertoire consisted of expanded T cell clones, differing markedly in composition from the relatively more polyclonal peripheral CD8 or CD4 T cell subsets found even in this elderly population. Twenty-four of the valveinfiltrating T cell clones also had the same clone identified in blood, some of which were highly expanded. Interestingly, 22 of these 24 shared clones were CD8 in lineage (p ‫؍‬ 1.5 ؋ 10 ؊12 ), suggesting a possible relationship to the expanded CD8 ؉ CD28 ؊ T cell clones frequently present in the elderly. Additionally, the sequences of several TCR ␤-chain CDR3 regions were homologous to TCR ␤-chains identified previously in allograft arteriosclerosis. We infer that these findings are inconsistent with a nonselective secondary response of T cells to inflammation and instead suggest that clonally expanded ␣␤ T cells are implicated in mediating a component of the valvular injury responsible for CAS.

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Section: Alcific Aortic Stenosis (Cas)mentioning

confidence: 99%

The Lymphocytic Infiltration in Calcific Aortic Stenosis Predominantly Consists of Clonally Expanded T Cells

Wu¹,

Maurer²,

Friedman³

et al. 2007

The Journal of Immunology

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“…Epidemiological risk factors of AS resemble those of atherosclerosis, including elevated serum LDL cholesterol, hypertension, smoking, diabetes, and male sex (1,3,4). Furthermore, LDL cholesterol accumulates in stenotic aortic valves (5-7), and experimental AS can be induced by dietary hypercholesterolemia in animal models (8)(9)(10)(11). Finally, LDL cholesterol and its oxidation products may stimulate local inflammation in the valves and may also accelerate cell proliferation, bone matrix production, and subsequent calcification of the valves (6,9,12).…”

mentioning

confidence: 99%

Accumulation of cholesterol precursors and plant sterols in human stenotic aortic valves

Helske

Miettinen

Gylling

et al. 2008

Journal of Lipid Research

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The pathogenesis of aortic valve stenosis (AS) is characterized by the accumulation of LDL-derived cholesterol in the diseased valves. Since LDL particles also contain plant sterols, we investigated whether plant sterols accumulate in aortic valve lesions. Serum samples were collected from 82 patients with severe AS and from 12 control subjects. Aortic valves were obtained from a subpopulation of 21 AS patients undergoing valve surgery and from 10 controls. Serum and valvular total cholesterol and noncholesterol sterols were measured by gas-liquid chromatography. Noncholesterol sterols, including both cholesterol precursors and sterols reflecting cholesterol absorption, were detected in serum samples and aortic valves. The higher the ratios to cholesterol of the cholesterol precursors and absorption markers in serum, the higher their ratios in the stenotic aortic valves (r 5 0.74, P , 0.001 for lathosterol and r 5 0.88, P , 0.001 for campesterol). The valvular ratio to cholesterol of lathosterol correlated negatively with the aortic valve area (r 5 20.47, P 5 0.045), suggesting attenuation of cholesterol synthesis with increasing severity of AS. The higher the absorption of cholesterol, the higher the plant sterol contents in stenotic aortic valves. These findings suggest that local accumulation of plant sterols and cholesterol precursors may participate in the pathobiology of aortic valve disease.

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“…Both CAVD lesions and atherosclerotic lesions contain inflammatory cells, with advanced lesions containing calcium deposits ). In addition, pathological studies of human stenotic valves have identified lesions similar to those in atherosclerotic plaques (Otto et al, 1994, Olsson et al, 1999, and similar lesions have been described in aortic valve leaflets of atherosclerosis in rabbits and mice (Tanaka et al, 2005, Aikawa et al, 2007b. But differences exist between the pathologies of CAVD and atherosclerosis.…”

Section: Pharmacological Treatmentmentioning

confidence: 84%

“…ApoE is a protein that allows for receptor-mediated removal of very low-density lipoprotein (VLDL) from the circulation. Spontaneous hypercholesterolemia occurs in ApoE -/-mice, and as they age, they demonstrate increased transvalvular velocity, aortic regurgitation, and nodular calcification (Tanaka et al, 2005). When subjected to a hypercholesterolemic diet, accelerated early disease is observed, characterized by thickened leaflets, activated endothelial cells, and subendothelial lesions rich in macrophages, which co-localize with MMPs, cathepsins, α-SMA, ALP, Runx2/Cbfa1, and osteocalcin expression (Aikawa et al, 2007a, Aikawa et al, 2007b.…”

Section: Murine Modelsmentioning

confidence: 99%