Progression of calcific aortic valve sclerosis in WHHLMI rabbits

Hara, Tetsuya; Tsukada, Norie; Okano, Mitsumasa; Ishida, Tatsuro; Hirata, Ken–ichi; Shiomi, Masashi

doi:10.1016/j.atherosclerosis.2018.03.044

Cited by 6 publications

(5 citation statements)

References 46 publications

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“…These include the synexpression genes of the Wnt, TGF-beta, and BMP signaling pathways. Similar to primary aortic valve interstitial cell cultures established from human patients suffering from calcific aortic valve disease, osteoprogeterin ( Opg ) expression was reduced in our mutants, while elevated Opg expression was described in a rabbit model for the stenotic aortic valve [ 47 ]. Although the gene encoding a key pro-chondrogenic transcription factor Sox9 did not show changes in overall expression levels, we could detect increased nuclear Sox9 immunostaining and elevated protein levels of its transcriptional target Aggrecan in mutant tissues, particularly in the leaflet–wall junction, where positive Alcian blue staining and hypertrophic chondrocyte-appearing cells could be seen in the mutants.…”

Section: Discussionmentioning

confidence: 97%

Activation of AcvR1-Mediated Signaling Results in Semilunar Valve Defects

Syed

Rajderkar

Mann

et al. 2022

JCDD

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Calcific aortic valve disease (CAVD) is a common cardiac defect, particularly in the aging population. While several risk factors, such as bi-leaflet valve structure and old age, have been identified in CAVD pathogenesis, molecular mechanisms resulting in this condition are still under active investigation. Bone morphogenetic protein signaling via the activin type I receptor (AcvRI) plays an important role during physiological and pathological processes involving calcification, e.g., bone formation and heterotopic ossification. In addition, AcvRI is required for normal cardiac valve development, yet its role in aortic valve disease, if any, is currently unknown. Here, we induced the expression of constitutively active AcvRI in developing mouse embryos in the endocardium and in cells at the valve leaflet–wall junction that are not of endocardium origin using the Nfac1Cre transgene. The mutant mice were born alive, but showed thickened aortic and pulmonary valve leaflets during the early postnatal period. Adult mutant mice developed aortic stenosis with high frequency, sclerotic aortic valves, and displayed Alcian Blue-positive hypertrophic chondrocyte-like cells at the leaflet–wall junction. Calcification was only seen with low penetrance. In addition, we observed that the expression levels of gene sets associated with inflammation-related cytokine signaling, smooth muscle cell contraction, and cGMP signaling were altered in the mutants when compared with those of the controls. This work shows that, in a mouse model, such continuous AcvRI activity in the Nfatc1Cre recombination domain results in pathological changes in the aortic valve structure and function.

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Section: Discussionmentioning

confidence: 97%

Activation of AcvR1-Mediated Signaling Results in Semilunar Valve Defects

Syed

Rajderkar

Mann

et al. 2022

JCDD

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“…There are a number of animal models of calcific aortic valve disease (CAVD) recapitulating distinct human hallmarks in diet-induced, genetic, congenital, and developmental mouse as well as rabbit and porcine models, each with its specific restrictions [ 22 , 50 ]. While diet-induced models often resemble changes in metabolic disorders with mild valvular impairment, some mice and rabbit models acquire hemodynamically significant calcific aortic valve disease, but the same has yet to be shown in pig for long-term follow up [ 2 ].…”

Section: Discussionmentioning

confidence: 99%

Multiparametric MRI identifies subtle adaptations for demarcation of disease transition in murine aortic valve stenosis

et al. 2022

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Aortic valve stenosis (AS) is the most frequent valve disease with relevant prognostic impact. Experimental model systems for AS are scarce and comprehensive imaging techniques to simultaneously quantify function and morphology in disease progression are lacking. Therefore, we refined an acute murine AS model to closely mimic human disease characteristics and developed a high-resolution magnetic resonance imaging (MRI) approach for simultaneous in-depth analysis of valvular, myocardial as well as aortic morphology/pathophysiology to identify early changes in tissue texture and critical transition points in the adaptive process to AS. AS was induced by wire injury of the aortic valve. Four weeks after surgery, cine loops, velocity, and relaxometry maps were acquired at 9.4 T to monitor structural/functional alterations in valve, aorta, and left ventricle (LV). In vivo MRI data were subsequently validated by histology and compared to echocardiography. AS mice exhibited impaired valve opening accompanied by significant valve thickening due to fibrotic remodelling. While control mice showed bell-shaped flow profiles, AS resulted not only in higher peak flow velocities, but also in fragmented turbulent flow patterns associated with enhanced circumferential strain and an increase in wall thickness of the aortic root. AS mice presented with a mild hypertrophy but unaffected global LV function. Cardiac MR relaxometry revealed reduced values for both T1 and T2 in AS reflecting subtle myocardial tissue remodelling with early alterations in mitochondrial function in response to the enhanced afterload. Concomitantly, incipient impairments of coronary flow reserve and myocardial tissue integrity get apparent accompanied by early troponin release. With this, we identified a premature transition point with still compensated cardiac function but beginning textural changes. This will allow interventional studies to explore early disease pathophysiology and novel therapeutic targets.

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“…This combination appears to provide a better model of CAVD than hypercholesterolemic or vitamin D diets alone ( Roosens et al, 2013a ). However, a rabbit model using high-cholesterol diet is limited by liver dysfunction and high mortality rates due to cholesterol overload ( Hara et al, 2018 ). In contrast, rabbit genetic models that have alterations in the Ldlr and/or apolipoprotein-encoding genes result in hypercholesterolemia even under a cholesterol-free, limited fat diet without cholesterol overload ( Sider et al, 2011 ).…”

Section: Animal Modelsmentioning

confidence: 99%

“…In contrast, rabbit genetic models that have alterations in the Ldlr and/or apolipoprotein-encoding genes result in hypercholesterolemia even under a cholesterol-free, limited fat diet without cholesterol overload ( Sider et al, 2011 ). Such a model is the Watanabe heritable hyperlipidemic rabbits that develop valve thickening, calcification, aortic stenosis and calcification-related gene activation ( Hara et al, 2018 ). In addition to the hypercholesterolemic models, a hypertensive rabbit model develops increased valve thickness and mild aortic stenosis ( Cuniberti et al, 2006 ).…”

Section: Animal Modelsmentioning

confidence: 99%

Models and Techniques to Study Aortic Valve Calcification in Vitro, ex Vivo and in Vivo. An Overview

Bogdanova

Zabirnyk²,

Malashicheva³

et al. 2022

Front. Pharmacol.

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Aortic valve stenosis secondary to aortic valve calcification is the most common valve disease in the Western world. Calcification is a result of pathological proliferation and osteogenic differentiation of resident valve interstitial cells. To develop non-surgical treatments, the molecular and cellular mechanisms of pathological calcification must be revealed. In the current overview, we present methods for evaluation of calcification in different ex vivo, in vitro and in vivo situations including imaging in patients. The latter include echocardiography, scanning with computed tomography and magnetic resonance imaging. Particular emphasis is on translational studies of calcific aortic valve stenosis with a special focus on cell culture using human primary cell cultures. Such models are widely used and suitable for screening of drugs against calcification. Animal models are presented, but there is no animal model that faithfully mimics human calcific aortic valve disease. A model of experimentally induced calcification in whole porcine aortic valve leaflets ex vivo is also included. Finally, miscellaneous methods and aspects of aortic valve calcification, such as, for instance, biomarkers are presented.

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Progression of calcific aortic valve sclerosis in WHHLMI rabbits

Cited by 6 publications

References 46 publications

Activation of AcvR1-Mediated Signaling Results in Semilunar Valve Defects

Activation of AcvR1-Mediated Signaling Results in Semilunar Valve Defects

Multiparametric MRI identifies subtle adaptations for demarcation of disease transition in murine aortic valve stenosis

Models and Techniques to Study Aortic Valve Calcification in Vitro, ex Vivo and in Vivo. An Overview

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