Progression of aortic valve stenosis: TGF-β1 is present in calcified aortic valve cusps and promotes aortic valve interstitial cell calcification via apoptosis

Jiang, Bo; Narula, Navneet; Li, Quanyi; Mohler, Emile R.; Levy, Robert J.

doi:10.1016/s0003-4975(02)04312-6

Cited by 398 publications

(354 citation statements)

References 21 publications

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“…Diseased valves have been shown previously to express the pleiotropic growth factor, TGF-β1 [32,30,45] and a mouse model of CAVD has demonstrated elevated levels of phosphorylated Smad transcription factors in aortic valves [46]. This study demonstrates that in human aortic valve lesions expression of both TGFβ1 and phosphorylated Smad2/3 are elevated throughout the thickened valve leaflets.…”

Section: Discussionsupporting

confidence: 50%

Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans

Osman

Grande-Allen

Ballinger

et al. 2013

Cardiovascular Pathology

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Section: Discussionsupporting

confidence: 50%

Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans

Osman

Grande-Allen

Ballinger

et al. 2013

Cardiovascular Pathology

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“…Hyperplastic lesions in mouse aortic valves in both models exhibited increased expression of TGF‐β1. Interestingly, TGF‐β signaling promotes VIC proliferation and mineralization in vitro and in a clinical setting 47, 48…”

Section: Discussionmentioning

confidence: 99%

Local Application of Leptin Antagonist Attenuates Angiotensin II–Induced Ascending Aortic Aneurysm and Cardiac Remodeling

Ben‐Zvi

Savion

Kolodgie

et al. 2016

JAHA

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BackgroundAscending thoracic aortic aneurysm (ATAA) is driven by angiotensin II (AngII) and contributes to the development of left ventricular (LV) remodeling through aortoventricular coupling. We previously showed that locally available leptin augments AngII‐induced abdominal aortic aneurysms in apolipoprotein E–deficient mice. We hypothesized that locally synthesized leptin mediates AngII‐induced ATAA.Methods and ResultsFollowing demonstration of leptin synthesis in samples of human ATAA associated with different etiologies, we modeled in situ leptin expression in apolipoprotein E–deficient mice by applying exogenous leptin on the surface of the ascending aorta. This treatment resulted in local aortic stiffening and dilation, LV hypertrophy, and thickening of aortic/mitral valve leaflets. Similar results were obtained in an AngII‐infusion ATAA mouse model. To test the dependence of AngII‐induced aortic and LV remodeling on leptin activity, a leptin antagonist was applied to the ascending aorta in AngII‐infused mice. Locally applied single low‐dose leptin antagonist moderated AngII‐induced ascending aortic dilation and protected mice from ATAA rupture. Furthermore, LV hypertrophy was attenuated and thickening of aortic valve leaflets was moderated. Last, analysis of human aortic valve stenosis leaflets revealed de novo leptin synthesis, whereas exogenous leptin stimulated proliferation and promoted mineralization of human valve interstitial cells in culture.ConclusionsAngII‐induced ATAA is mediated by locally synthesized leptin. Aortoventricular hemodynamic coupling drives LV hypertrophy and promotes early aortic valve lesions, possibly mediated by valvular in situ leptin synthesis. Clinical implementation of local leptin antagonist therapy may attenuate AngII‐induced ATAA and moderate related LV hypertrophy and pre–aortic valve stenosis lesions.Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00449306.

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“…CAS is characterized by valve thickening and stenosis of the orifice area triggered by an overactive inflammatory process involving expression of cytokines, including tumor necrosis factor-a (TNF-a) [2], transforming growth factor-beta 1 [3], and interleukin-1 beta (IL-1beta) [4]. These cytokines contribute to extracellular matrix formation, remodeling, and ectopic calcification, which are accelerated in the presence of high inorganic phosphate (2.2-3.2 mM) [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

CD34-negative mesenchymal stem-like cells may act as the cellular origin of human aortic valve calcification

Nomura

Seya

et al. 2013

Biochemical and Biophysical Research Communications

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Although various osteogenic inducers contribute to the calcification of human aortic valve interstitial cells, the cellular origin of calcification remains unclear. We immunohistochemically investigated the cellular origin of valve calcification using enzymatically isolated cells from both calcified and non-calcified human aortic valve specimens. CD73-, 90-, and 105-positive and CD45-negative mesenchymal stem-like cells (MSLCs) were isolated from both types of valve specimens using fluorescence-activated cell sorting. MSLCs were further sorted into CD34-negative and -positive cells. Compared with CD34-positive cells, CD34-negative MSLCs were significantly more sensitive to high inorganic phosphate (3.2 mM), calcifying easily in response. Furthermore, immunohistochemical staining showed that significantly higher numbers (～7-9-fold) of CD34-negative compared with CD34-positive MSLCs were localized in calcified aortic valve specimens obtained from calcified aortic stenosis patients. These results suggest that CD34-negative MSLCs are responsible for calcification of the aortic valve.

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Progression of aortic valve stenosis: TGF-β1 is present in calcified aortic valve cusps and promotes aortic valve interstitial cell calcification via apoptosis

Cited by 398 publications

References 21 publications

Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans

Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans

Local Application of Leptin Antagonist Attenuates Angiotensin II–Induced Ascending Aortic Aneurysm and Cardiac Remodeling

CD34-negative mesenchymal stem-like cells may act as the cellular origin of human aortic valve calcification

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