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

Abstract

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.

Keywords: Aortic valve; Calcification; NADPH oxidases; Oxidative stress; Reactive oxygen species.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Figures

Figure 1

Pathogenesis of initiation and propagation of CAVD and potential roles of ROS. CAVD is initiated by valve endothelial cells (VEC) damage, triggered by diverse disease stimuli such as systemic inflammation, hyperlipidaemia, mechanical and shear stress, and other risk factors including ageing, hypertension, obesity, and diabetes. These permit the infiltration and oxidation of lipoproteins, and extravasation of inflammatory cells and subsequently innate and adaptive immune responses. In the propagation phase of the disease fibrosis and calcification occur, triggered by the release of cytokines that induce the transition of VICs into myofibroblasts and osteoblasts via the up-regulation of a number of fibrotic and osteogenic genes, respectively. Differentiation of VICs into myofibroblasts leads to leaflet thickening and fibrosis, due to extracellular matrix remodelling containing increased collagen and decreased elastin, forming a scaffold upon which amorphous deposition occurs. VIC transformation into osteoblasts is promoted further by a number of mechanisms including the down-regulation of and/or mutations in NOTCH1, which impair the ability of NOTCH1 to suppress osteogenic gene expression, up-regulated WNT/β-catenin signalling, and increased receptor activator of nuclear factor kappa B (RANK)/RANK ligand (RANKL) interactions. These differentiated VICs secrete calcifying microvesicles that promote calcium phosphate nucleation within valve leaflets. Apoptotic bodies released from VICs driven to programmed cell death by inflammatory cytokines and up-regulated ectonucleotidase expression act as a nidus for calcium and phosphorous crystal deposition. Adverse accumulation of ROS from a variety of sources mediates the oxidation of infiltrating lipids and inflammatory response in the initiation phase of CAVD. ROS are also critically implicated in the propagation phase of the disease, mediating the differentiation of VICs by up-regulating the expression of a series of osteogenic and fibrotic genes via a number of intracellular signalling cascades outlined in the main text. ATP, adenosine triphosphate; AMP, adenosine monophosphate; BAV, bicuspid aortic valve; BMP2, bone morphogenic protein2; ENPP1, ectonucleotide pyrophosphatase/phosphodiesterase family member 1; IL, interleukin; LDL, low-density lipoprotein; Lp(a), lipoprotein a; ROS, reactive oxygen species; NOTCH1, notch homolog 1, translocation-associated; PPi, inorganic pyrophosphate; RUNX2, runt-related transcription factor 2; SOX9, SRY-box 9; TGF-β, transforming growth factor beta; TNFα, tumour necrosis factor alpha.

Figure 2

Nitric oxide synthase in the pathophysiology of calcific aortic valve disease. Uncoupling of endothelial nitric oxide synthase (eNOS) reduces nitric oxide bioavailability and increases superoxide O2−(O2) generation. In combination with superoxide generated from other sources, such as nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), there is increased peroxynitrite (ONOO−) formation as it reacts with residual NO. In a positive feedback loop, this induces further NOS uncoupling via peroxynitrite-mediated oxidation of the obligatory nitric oxide synthase co-factor tetrahydrobiopterin. Peroxynitrite is also implicated in evoking DNA damage and dysregulated DNA repair responses leading to the up-regulated expression of osteogenic genes and valvular calcification.

Figure 3

The adverse sources of ROS and potential therapeutic implications in CAVD. Pre-clinical and human studies implicate several adverse sources of ROS in the pathophysiology of CAVD. Intracellular ROS accumulation induces the activation of a variety of signalling cascades that increase the expression of osteogenic and fibrotic genes, phenotypically transforming aortic valvular interstitial cells and leading to valvular calcification and fibrosis. Several potential therapeutic strategies that seek to inhibit ROS-mediated oxidative stress have been suggested. AKT, protein kinase B; BH4, tetrahydrobiopterin; CNPs, cerium oxide nanoparticles; DETA-NONOate, 2,2'-(2-Hydroxy-2 nitrosohydrazinylidene)bis-ethanamine; ERK, extracellular signal-regulated kinases; GS3β, glycogen synthase kinase 3 beta; L-NAME, L-NG-Nitroarginine methyl ester; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase; Mito, mitochondria; MnBuOE, Mn(III) meso-tetrakis (N-n-butoxyethylpyridinium-2-yl) porphyrin; NOS, nitric oxide synthase; NOX2, reduced nicotinamide adenine dinucleotide phosphate oxidase 2; Peg-Catalase, polyethylene glycol-catalase; Peg-SOD, polyethylene glycol-superoxide dismutase; ROS, reactive oxygen species; SSAO, semicarbazide-sensitive amine oxidase; SNP, sodium nitroprusside; XOS, xanthine oxidase.