Nitric oxide prevents aortic valve calcification by S-nitrosylation of USP9X to activate NOTCH signaling

Majumdar, Uddalak; Manivannan, Sathiyanarayanan; Basu, Madhumita; Ueyama, Yukie; Blaser, Mark C.; Cameron, Emily; McDermott, Michael R.; Lincoln, Joy; Cole, Susan E.; Wood, Stephen A.; Aïkawa, Elena; Lilly, Brenda; Garg, Vidu

doi:10.1126/sciadv.abe3706

Cited by 47 publications

(66 citation statements)

References 59 publications

(85 reference statements)

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“…Endothelial-derived NO inhibits calcification of porcine aortic VICs in vitro and modulates Notch1 signalling ( 74 ). Post-translational modification of the deubiquitinase USP9X has been demonstrated as a mechanism for NO-mediated inhibition of myofibroblastic porcine aortic VIC differentiation ( 75 ). In models of vascular calcification, endothelial-derived NO inhibits TGFβ signalling in vascular smooth muscle cells, which may be an additional mechanism by which NO signalling inhibits pathological VIC differentiation ( 76 ).…”

Section: The Role Of Valvular Endothelial Cells In Development Of Cal...mentioning

confidence: 99%

Uncoupling the Vicious Cycle of Mechanical Stress and Inflammation in Calcific Aortic Valve Disease

Dayawansa

Baratchi

Peter

2022

Front. Cardiovasc. Med.

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Calcific aortic valve disease (CAVD) is a common acquired valvulopathy, which carries a high burden of mortality. Chronic inflammation has been postulated as the predominant pathophysiological process underlying CAVD. So far, no effective medical therapies exist to halt the progression of CAVD. This review aims to outline the known pathways of inflammation and calcification in CAVD, focussing on the critical roles of mechanical stress and mechanosensing in the perpetuation of valvular inflammation. Following initiation of valvular inflammation, dysregulation of proinflammatory and osteoregulatory signalling pathways stimulates endothelial-mesenchymal transition of valvular endothelial cells (VECs) and differentiation of valvular interstitial cells (VICs) into active myofibroblastic and osteoblastic phenotypes, which in turn mediate valvular extracellular matrix remodelling and calcification. Mechanosensitive signalling pathways convert mechanical forces experienced by valve leaflets and circulating cells into biochemical signals and may provide the positive feedback loop that promotes acceleration of disease progression in the advanced stages of CAVD. Mechanosensing is implicated in multiple aspects of CAVD pathophysiology. The mechanosensitive RhoA/ROCK and YAP/TAZ systems are implicated in aortic valve leaflet mineralisation in response to increased substrate stiffness. Exposure of aortic valve leaflets, endothelial cells and platelets to high shear stress results in increased expression of mediators of VIC differentiation. Upregulation of the Piezo1 mechanoreceptor has been demonstrated to promote inflammation in CAVD, which normalises following transcatheter valve replacement. Genetic variants and inhibition of Notch signalling accentuate VIC responses to altered mechanical stresses. The study of mechanosensing pathways has revealed promising insights into the mechanisms that perpetuate inflammation and calcification in CAVD. Mechanotransduction of altered mechanical stresses may provide the sought-after coupling link that drives a vicious cycle of chronic inflammation in CAVD. Mechanosensing pathways may yield promising targets for therapeutic interventions and prognostic biomarkers with the potential to improve the management of CAVD.

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Section: The Role Of Valvular Endothelial Cells In Development Of Cal...mentioning

confidence: 99%

Uncoupling the Vicious Cycle of Mechanical Stress and Inflammation in Calcific Aortic Valve Disease

Dayawansa

Baratchi

Peter

2022

Front. Cardiovasc. Med.

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“…Indeed, NO synthesis and signaling are markedly affected by the oscillatory shear stress in the endothelium lining the calcification-prone fibrosa compared with the disease-resilient ventricularis [ 25 ]. In vivo studies have shown that a lack of eNOS in mice promotes a CAVD-like phenotype [ 26 ], whereas restoring paracrine NO signaling blunts VIC-driven calcification in different experimental models [ 27 ]. Furthermore, studies have also reported that NO maintains valvular homeostasis through guanylyl cyclase/cGMP- and NOTCH1-dependent mechanisms [ 28 , 29 ].…”

Section: Role Of Lipoprotein(a) and Oxidized Phospholipids In Cavdmentioning

confidence: 99%

Implication of Lipids in Calcified Aortic Valve Pathogenesis: Why Did Statins Fail?

Nsaibia

Devendran

Goubaa

et al. 2022

JCM

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Calcific Aortic Valve Disease (CAVD) is a fibrocalcific disease. Lipoproteins and oxidized phospholipids play a substantial role in CAVD; the level of Lp(a) has been shown to accelerate the progression of valve calcification. Indeed, oxidized phospholipids carried by Lp(a) into the aortic valve stimulate endothelial dysfunction and promote inflammation. Inflammation and growth factors actively promote the synthesis of the extracellular matrix (ECM) and trigger an osteogenic program. The accumulation of ECM proteins promotes lipid adhesion to valve tissue, which could initiate the osteogenic program in interstitial valve cells. Statin treatment has been shown to have the ability to diminish the death rate in subjects with atherosclerotic impediments by decreasing the serum LDL cholesterol levels. However, the use of HMG-CoA inhibitors (statins) as cholesterol-lowering therapy did not significantly reduce the progression or the severity of aortic valve calcification. However, new clinical trials targeting Lp(a) or PCSK9 are showing promising results in reducing the severity of aortic stenosis. In this review, we discuss the implication of lipids in aortic valve calcification and the current findings on the effect of lipid-lowering therapy in aortic stenosis.

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“…Increasing NO bioavailability not only reduces the burden of ROS but also regulates Notch1 signalling and its nuclear localization to reduce the expression of osteogenic markers in VICs. 283 , 284 …”

Section: Targeting Ros In Cavdmentioning

confidence: 99%

Role of oxidative stress in calcific aortic valve disease and its therapeutic implications

Greenberg

Zhao

Shah

et al. 2021

Cardiovascular Research

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Calcific aortic valve disease (CAVD) is the end result of active cellular processes that lead to the progressive fibrosis and calcification of aortic valve leaflets. In western populations, CAVD is a significant cause of cardiovascular morbidity and mortality, and in the absence of effective drugs, it will likely represent an increasing disease burden as populations age. As there are currently no pharmacological therapies available for preventing, treating, or slowing the development of CAVD, understanding the mechanisms underlying the initiation and progression of the disease is important for identifying novel therapeutic targets. Recent evidence has emerged of an important causative role for reactive oxygen species (ROS)-mediated oxidative stress in the pathophysiology of CAVD, inducing the differentiation of valve interstitial cells into myofibroblasts and then osteoblasts. In this review we focus on the roles and sources of ROS driving CAVD and consider their potential as novel therapeutic targets for this debilitating condition.

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Nitric oxide prevents aortic valve calcification by S-nitrosylation of USP9X to activate NOTCH signaling

Cited by 47 publications

References 59 publications

Uncoupling the Vicious Cycle of Mechanical Stress and Inflammation in Calcific Aortic Valve Disease

Uncoupling the Vicious Cycle of Mechanical Stress and Inflammation in Calcific Aortic Valve Disease

Implication of Lipids in Calcified Aortic Valve Pathogenesis: Why Did Statins Fail?

Role of oxidative stress in calcific aortic valve disease and its therapeutic implications

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