Neoangiogenesis, T-lymphocyte infiltration, and heat shock protein-60 are biological hallmarks of an immunomediated inflammatory process in end-stage calcified aortic valve stenosis

Mazzone, Annamaria; Epistolato, Maria Carmela; Caterina, Raffaele De; Storti, Simona; Vittorini, Simona; Sbrana, Silverio; Gianetti, Jacopo; Bevilacqua, Stefano; Glauber, Mattia; Biagini, Andrea; Tanganelli, Piero

doi:10.1016/j.jacc.2003.12.041

Cited by 119 publications

(93 citation statements)

References 30 publications

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“…17 Indeed, neovascularization of the normally avascular valve tissue is a prominent feature of aortic stenosis. 7,18 Interestingly, in the stenotic valves, the cells surrounding the neovessels were cystatin C positive, but the neovessels themselves were cystatin C negative ( Figure 5M through 5O). These findings suggest that cathepsins and cystatin C may regulate the growth of microvessels during the progression of aortic stenosis and that a local imbalance of elastolytic cathepsins and their inhibitor cystatin C may have promoted neovessel formation in the stenotic aortic valves.…”

Section: Discussionmentioning

confidence: 98%

“…14 -16 Because cathepsin S was shown recently to participate in ECM degradation during microvessel formation, 17 this cathepsin and perhaps also other cathepsins may participate in neoangiogenesis, a process critical for progression of aortic stenosis. 7,18 The possible role of cathepsins and cystatin C in the pathogenesis of aortic stenosis has not been examined previously. Moreover, there are no data available on the possible role of the elastolytic protease cathepsin V in cardiovascular diseases.…”

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confidence: 99%

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Increased Expression of Elastolytic Cathepsins S, K, and V and Their Inhibitor Cystatin C in Stenotic Aortic Valves

Helske

Syväranta

Lindstedt

et al. 2006

ATVB

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Objective-To investigate the possible role of elastolytic cathepsins S, K, and V and their endogenous inhibitor cystatin C in adverse extracellular matrix remodeling of stenotic aortic valves. Methods and Results-Stenotic aortic valves were collected at valve replacement surgery and control valves at cardiac transplantations. The expression of cathepsins S, K, and V and cystatin C was studied by conventional and real-time polymerase chain reaction and by immunohistochemistry. Total cathepsin activity in the aortic valves was quantified by a fluorometric microassay. When compared with control valves, stenotic valves showed increased mRNA expression of cathepsins S, K, and V (PϽ0.05 for each) and a higher total cathepsin activity (PϽ0.001). In stenotic valves, cystatin C mRNA was increased (PϽ0.05), and cystatin C protein was found particularly in areas with infiltrates of inflammatory cells. Both cathepsin S and cystatin C were present in bony areas of the valves, whereas cathepsin V localized to endothelial cells in areas rich of neovascularization. Incubation of thin sections of aortic valves with cathepsins S, K, and V resulted in severe disruption of elastin fibers, and this cathepsin effect could be blocked by adding cystatin C to the incubation system. Key Words: aortic stenosis Ⅲ cathepsin Ⅲ cystatin C Ⅲ elastin Ⅲ heart valves A ortic stenosis is an active inflammatory process resembling atherosclerosis. The pathophysiological changes in the stenotic aortic valves include inflammatory cell infiltration, neoangiogenesis, accumulation of lipids, and active mediators of calcification with extracellular matrix (ECM) degradation. 1-7 Furthermore, aortic valvular myofibroblasts undergo phenotypic changes toward an osteoblast-like phenotype, and active bone formation and remodeling occur in the stenotic valves. 8,9 These processes lead to loss of normal valvular geometry, disruption of the elastic fibers, and accumulation of fibrocalcific masses. This adverse remodeling of the valves is associated with the loss of their mechanical and elastic properties, leading to thickening and stiffening of the valve leaflets and to progression of aortic stenosis. Conclusions-StenoticThe pathophysiological mechanisms involved in the abnormal accumulation and degradation of ECM in the valves are incompletely understood. In atherosclerotic lesions, elastolytic cysteine proteases, including cathepsins S and K, are overexpressed at sites of arterial elastin damage, whereas their endogenous inhibitor, cystatin C, is severely reduced. 10,11 Moreover, a marked deficiency of cystatin C expression with accentuated cathepsin S and K expression in aortic aneurysms and a negative correlation of cystatin C serum levels with the diameter of abdominal aorta has been reported. 11 These observations support the role of an imbalance between cathepsins and cystatin C in diseases characterized by pathological elastin degradation. In addition, cathepsin K has a crucial role in bone matrix degradation necessary for normal bone growth and remodeling...

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

Increased Expression of Elastolytic Cathepsins S, K, and V and Their Inhibitor Cystatin C in Stenotic Aortic Valves

Helske

Syväranta

Lindstedt

et al. 2006

ATVB

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“…Следует отме-тить, что TNF-α в эксперименте наиболее интен-сивно индуцировал накопление кальция в тех клапа-нах, где уже начался процесс АС, что свидетельствует о возможной генетической/эпигенетической регуля-ции степени выраженности порока [45]. С точки зре-ния генетических исследований TNF-α, известно лишь о повышенном уровне экспрессии гена в АК [46], так же, как и в отношении ICAM-1, молекул адгезии сосудистого эндотелия 1 типа (vascular cell adhesion molecule-1 -VCAM-1) и hsp60 [47].…”

Section: кальциевый обменunclassified

“…В своей работе они показали, что наличие мутации Q192R в гене PON1 связано с развитием АС (р=0,03) [56] Молекулярно-генетические механизмы неоангиогенеза в АК при АС Наличие процессов неоангиогенеза в патогенезе АС подтверждается во многих исследованиях [47,[57][58][59]. Так, фактор роста сосудистого эндотелия VEGF и его два рецептора Flt1 и Klk1 ассоциированы с процессами неореваскуляризации в АК при АС [57,58].…”

Section: кальциевый обменunclassified

Molecular-Genetic Factors, Associated With Aortic Stenosis Development

Tipteva¹,

Чумакова²,

Затейщиков³

2015

Ross. kardiol. ž.

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“…12,29 Several studies have established the occurrence of neovascularization during CAVD. 11,18,31 There has been little investigation, however, into how the cell-mediated mechanisms that underlie vascular angiogenesis play a role in the pathology of CAVD. During valve development and normal endothelial-to-mesenchymal transformation (EndMT), valve endothelial cells (VECs) undergo a physiological transdifferentiation that shares several characteristics with the process of vascular angiogenic root formation.…”

Section: Introductionmentioning

confidence: 99%

Valve Interstitial Cells Act in a Pericyte Manner Promoting Angiogensis and Invasion by Valve Endothelial Cells

et al. 2016

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Neovascularization is an understudied aspect of calcific aortic valve disease (CAVD). Within diseased valves, cells along the neovessels' periphery stain for pericyte markers, but it is unclear whether valvular interstitial cells (VICs) can demonstrate a pericyte-like phenotype. This investigation examined the perivascular potential of VICs to regulate valve endothelial cell (VEC) organization and explored the role of Angiopoeitin1-Tie2 signaling in this process. Porcine VECs and VICs were fluorescently tracked and co-cultured in Matrigel over 7 days. VICs regulated early VEC network organization in a ROCK-dependent manner, then guided later VEC network contraction through chemoattraction. Unlike vascular control cells, the valve cell cultures ultimately formed invasive spheroids with 3D angiogenic-like sprouts. VECs co-cultured with VICs displayed significantly more invasion than VECs alone; with VICs generally leading and wrapping around VEC invasive sprouts. Lastly, Angiopoietin1-Tie2 signaling was found to regulate valve cell organization during VEC/VIC spheroid formation and invasion. VICs demonstrated pericyte-like behaviors toward VECs throughout sustained co-culture. The change from a vasculogenic network to an invasive sprouting spheroid suggests that both cell types undergo phenotypic changes during long-term culture in the model angiogenic environment. Valve cells organizing into spheroids and undergoing 3D invasion of Matrigel demonstrated several typical angiogenic-like phenotypes dependent on basal levels of Angiopoeitin1-Tie2 signaling and ROCK activation. These results suggest that the ectopic sustained angiogenic environment during the early stages of valve disease promotes organized activity by both VECs and VICs, contributing to neovessel formation and the progression of CAVD.

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Neoangiogenesis, T-lymphocyte infiltration, and heat shock protein-60 are biological hallmarks of an immunomediated inflammatory process in end-stage calcified aortic valve stenosis

Cited by 119 publications

References 30 publications

Increased Expression of Elastolytic Cathepsins S, K, and V and Their Inhibitor Cystatin C in Stenotic Aortic Valves

Increased Expression of Elastolytic Cathepsins S, K, and V and Their Inhibitor Cystatin C in Stenotic Aortic Valves

Molecular-Genetic Factors, Associated With Aortic Stenosis Development

Valve Interstitial Cells Act in a Pericyte Manner Promoting Angiogensis and Invasion by Valve Endothelial Cells

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