Shear-Sensitive Genes in Aortic Valve Endothelium

Abstract

Significance: Currently, calcific aortic valve disease (CAVD) is only treatable through surgical intervention because the specific mechanisms leading to the disease remain unclear. In this review, we explore the forces and structure of the valve, as well as the mechanosensors and downstream signaling in the valve endothelium known to contribute to inflammation and valve dysfunction. Recent Advances: While the valvular structure enables adaptation to dynamic hemodynamic forces, these are impaired during CAVD, resulting in pathological systemic changes. Mechanosensing mechanisms-proteins, sugars, and membrane structures-at the surface of the valve endothelial cell relay mechanical signals to the nucleus. As a result, a large number of mechanosensitive genes are transcribed to alter cellular phenotype and, ultimately, induce inflammation and CAVD. Transforming growth factor-b signaling and Wnt/b-catenin have been widely studied in this context. Importantly, NADPH oxidase and reactive oxygen species/reactive nitrogen species signaling has increasingly been recognized to play a key role in the cellular response to mechanical stimuli. In addition, a number of valvular microRNAs are mechanosensitive and may regulate the progression of CAVD. Critical Issues: While numerous pathways have been described in the pathology of CAVD, no treatment options are available to avoid surgery for advanced stenosis and calcification of the aortic valve. More work must be focused on this issue to lead to successful therapies for the disease. Future Directions: Ultimately, a more complete understanding of the mechanisms within the aortic valve endothelium will lead us to future therapies important for treatment of CAVD without the risks involved with valve replacement or repair. Antioxid. Redox Signal. 25, 401-414.

Acidic extracellular environment affects miRNA expression in tumors in vitro and in vivo

“…Cytokines can affect the expression of miRNAs, a process by which the activation of the membrane receptors modulates the miRNA transcription for instance via a second messenger cascade . Finally, external physical (e.g., shear stress) or chemical stimuli are known to modulate the expression of non‐coding RNAs. One of the best studied parameters is the role of the O 2 partial pressure (pO 2 ) or tissue hypoxia.…”

Shape-Specific Nanoceria Mitigate Oxidative Stress-Induced Calcification in Primary Human Valvular Interstitial Cell Culture

“…15 ROS have also been shown to induce fibrosis and mineralization by promoting pro-fibrotic and pro-osteogenic signaling pathways such as AKT pathway and TGF- β pathway. 16,17 Furthermore, adenoviral transduction of catalase (CAT), a key antioxidant enzyme, decreased oxidative stress-induced differentiation of quiescent or myofibroblastic VICs into osteogenic phenotype and reduced calcific nodule deposition in human valve sclerosis-derived cells. 18 However, the benefits of antioxidant therapies, which directly target oxidative stress to treat valve calcification, are yet to be studied.…”

Epigenome alterations in aortic valve stenosis and its related left ventricular hypertrophy

“…It is well known that NOTCH1 regulates calcification related gene networks in human vascular and valvular endothelium [ 63 ]. Notably, NOTCH1 signaling is higher on the ventricular side, and it is considered protective for calcification [ 64 , 65 ]. Furthermore, human NOTCH1 mutations can cause both familial and sporadic AS disease [ 66 ].…”

“… HAVECs b [ 63 ], ↓ AS [ 99 ] Helicase like transcription factor; SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin, Subfamily A, Member 3; HLTF Chromatin remodeling cofactor, member of the SWI/SNF family, acts as a ubiquitin ligase for ‘Lys-63’-linked polyubiquitination of chromatin-bound PCNA. Blood dried spots- congenital AS [ 42 ] IKAROS family zinc finger 1; IKZF1 Chromatin remodeling ↑ BAVc vs. TAVn, ↑ TAVc vs. TAVn [ 182 ] Inhibitor of growth family member 3; ING3 Chromatin remodeling, HAT cofactor, component of the NUA4 HAT complex, binds H3K4me3 histone marks ↑ HAVICs 1 [ 78 ], ↓ AS [ 88 ], ↓ PAVECs* [ 177 ] INO80 complex subunit C; INO80C Chromatin remodeling cofactor, component of the INO80 chromatin remodeling complex ↑ HAVICs 1 [ 78 ] Janus Kinase 2; JAK2 Phosphorylation of Tyr(Y)-41 of histone H3 (H3T41 → H3Y41ph) ↑ rat AVICs*** [ 64 ] Jade family PHD finger 1; JADE1 /PHF17 Histone acetylation (H3, H4 → H3ac, H4ac), component of HBO1 HAT complex ↓ AS [ 99 ] Jade Family PHD Finger 2; JADE2 Histone acetylation (H3, H4 → H3ac, H4ac), component of HBO1 HAT complex HAVECs c [ 77 ] Arginine demethylase and lysine hydroxylase; JMJD6 Histone arginine demethylase (H3R2me, H4R3me → H3R2, H4R3) and a lysyl-hydroxylase. ↑ PAVICs # [ 178 ] Lysine acetyltransferase 2A; KAT2A /GCN5 HAT HAVECs c [ 77 ], ↓ PAVECs* [ 177 ] Lysine acetyltransferase 2B; KAT2B HAT HAVECs b [ 63 ], ↑ HAVICs 1 [ …”