Aortic valve disease and gamma-glutamyltransferase: Accumulation in tissue and relationships with calcific degeneration

Cappelli, Stefania; Epistolato, Maria Carmela; Vianello, Annamaria; Mazzone, Annamaria; Glauber, Mattia; Franzini, Maria; Ottaviano, Virginia; Pompella, Alfonso; Paolicchi, Aldo; Tanganelli, Piero

doi:10.1016/j.atherosclerosis.2010.08.063

Cited by 15 publications

(9 citation statements)

References 44 publications

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“…Because of its known role in matrix degradation and our group’s previous work in this area, we focused on TIMP3 for further study. TIMP3 is an inhibitor of extracellular matrix degradation through MMP inhibition that potentially links previous studies describing increased ECM degradation in stenotic or calcific valves compared to healthy valves 9,10 . As a functional readout of matrix remodeling in HAVECs, we used the DQ gelatin substrate in the gelatinase assay 25 , which has been shown to correlate with MMP activity and matrix degradation 15 .…”

Section: Resultsmentioning

confidence: 59%

Mechanosensitive microRNA-181b Regulates Aortic Valve Endothelial Matrix Degradation by Targeting TIMP3

Heath

Esmerats

Khambouneheuang

et al. 2017

Cardiovasc Eng Tech

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Calcific aortic valve disease (CAVD) is a major cause of morbidity in the aging population, but the underlying mechanisms of its progression remain poorly understood. Aortic valve calcification preferentially occurs on the fibrosa, which is subjected to disturbed flow. The side-specific progression of the disease is characterized by inflammation, calcific lesions, and extracellular matrix (ECM) degradation. Here, we explored the role of mechanosensitive microRNA-181b and its downstream targets in human aortic valve endothelial cells (HAVECs). Mechanistically, miR-181b is upregulated in OS and fibrosa, and it targets TIMP3, SIRT1, and GATA6, correlated with increased gelatinase/MMP activity. Overexpression of miR-181b led to decreased TIMP3 and exacerbated MMP activity as shown by gelatinase assay, and miR-181b inhibition decreased gelatinase activity through the repression of TIMP3 levels. Luciferase assay showed specific binding of miR-181b to the TIMP3 gene. Overexpression of miR-181b in HAVECs subjected to either LS or OS increased MMP activity, and miR-181b inhibition abrogated shear-sensitive MMP activity. These studies suggest that targeting this shear-dependent miRNA may provide a novel noninvasive treatment for CAVD.

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Section: Resultsmentioning

confidence: 59%

Mechanosensitive microRNA-181b Regulates Aortic Valve Endothelial Matrix Degradation by Targeting TIMP3

Heath

Esmerats

Khambouneheuang

et al. 2017

Cardiovasc Eng Tech

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“…On the contrary, smooth muscle-specific Runx2 deficiency down-regulated the expression of RANKL and was accompanied by decreased macrophage infiltration and reduced formation of osteoclast-like cells in the calcified lesions [122]. TRAP-positive cells have been previously observed in atherosclerotic lesions [157], [158], however, their origin and functions are unknown. Our studies provided the evidence that VSMC-derived RANKL promoted macrophage migration and differentiation into osteoclasts [122], [123], suggesting potential roles of RANKL-induced macrophage-derived osteoclasts in the atherosclerotic lesions [159].…”

Section: Regulation Of H2o2 Production In Vsmcmentioning

confidence: 97%

Redox signaling in cardiovascular pathophysiology: A focus on hydrogen peroxide and vascular smooth muscle cells

2016

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Oxidative stress represents excessive intracellular levels of reactive oxygen species (ROS), which plays a major role in the pathogenesis of cardiovascular disease. Besides having a critical impact on the development and progression of vascular pathologies including atherosclerosis and diabetic vasculopathy, oxidative stress also regulates physiological signaling processes. As a cell permeable ROS generated by cellular metabolism involved in intracellular signaling, hydrogen peroxide (H2O2) exerts tremendous impact on cardiovascular pathophysiology. Under pathological conditions, increased oxidase activities and/or impaired antioxidant systems results in uncontrolled production of ROS. In a pro-oxidant environment, vascular smooth muscle cells (VSMC) undergo phenotypic changes which can lead to the development of vascular dysfunction such as vascular inflammation and calcification. Investigations are ongoing to elucidate the mechanisms for cardiovascular disorders induced by oxidative stress. This review mainly focuses on the role of H2O2 in regulating physiological and pathological signals in VSMC.

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“…This finding is markedly different from observations in advanced atherosclerotic lesions, where activity of osteoblast-like cells is markedly reduced by statins 23 , but calcium deposits are resistant to reduction and/or resorption 193, 194 . These contrasting effects in valves and arteries are somewhat surprising because osteoclast-like cells are present in both calcifying aortic valves 79, 195–197 and in arteries 198, 199 . Further work to examine differences in calcified plaque composition/ultrastructure, and differences in osteoblast-/osteoclast-like function in arteries and valves, will be important to understanding the susceptibility of calcified deposits to resorption in different cardiovascular tissues.…”

Section: Histological and Molecular Changes With Treatment Of Valve Dmentioning

confidence: 99%

Calcific Aortic Valve Stenosis: Methods, Models, and Mechanisms

Miller

Weiß

Heistad

2011

Circulation Research

277

218

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Calcific aortic valve stenosis (CAVS) is a major health problem facing aging societies. The identification of osteoblast-like and osteoclast-like cells in human tissue has led to a major paradigm shift in the field. CAVS was thought to be a passive, degenerative process, whereas now the progression of calcification in CAVS is considered to be actively regulated. Mechanistic studies examining the contributions of true ectopic osteogenesis, non-osseous calcification, and ectopic osteoblast-like cells (that appear to function differently from skeletal osteoblasts) to valvular dysfunction have been facilitated by the development of mouse models of CAVS. Recent studies also suggest that valvular fibrosis, as well as calcification, may play an important role in restricting cusp movement, and CAVS may be more appropriately viewed as a fibrocalcific disease. High resolution echocardiography and magnetic resonance imaging have emerged as useful tools for testing the efficacy of pharmacological and genetic interventions in vivo. Key studies in humans and animals are reviewed that have shaped current paradigms in the field of CAVS, and suggest promising future areas for research.

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Aortic valve disease and gamma-glutamyltransferase: Accumulation in tissue and relationships with calcific degeneration

Cited by 15 publications

References 44 publications

Mechanosensitive microRNA-181b Regulates Aortic Valve Endothelial Matrix Degradation by Targeting TIMP3

Mechanosensitive microRNA-181b Regulates Aortic Valve Endothelial Matrix Degradation by Targeting TIMP3

Redox signaling in cardiovascular pathophysiology: A focus on hydrogen peroxide and vascular smooth muscle cells

Calcific Aortic Valve Stenosis: Methods, Models, and Mechanisms

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