Histone deacetylase 6 reduction promotes aortic valve calcification via an endoplasmic reticulum stress-mediated osteogenic pathway

Abstract

Objective: Aortic valve (AoV) calcification occurs via a pathophysiologic process that includes osteoblastic differentiation of valvular interstitial cells (VICs). Histone deacetylases (HDACs) have been shown to be involved in the pathogenesis of vascular diseases. Here, we investigated the role of HDAC6 in AoV calcification.Methods: AoV cusps from patients with aortic stenosis (n ¼ 7) and normal controls (n ¼ 7) were subjected to determination of calcified nodules and HDAC6 expression. Human VICs were cultured in osteogenic media and treated with 10 uM tubacin or HDAC6 small interfering RNA silencing to inhibit HDAC6. Treatment with 100 uM tauroursodeoxycholic acid was used to suppress endoplasmic reticulum stress. Activating transcription factor 4 (ATF4) small interfering RNAwas used to knock down ATF4. Alizarin red staining was used to evaluate calcified nodules formation of VICs cultured with osteogenic media for 14 days.Results: HDAC6 expression was significantly reduced in AoV tissue of patients with aortic stenosis compared with controls. Tubacin treatment or HDAC6 silencing markedly promoted osteoblastic differentiation accompanied by endoplasmic reticulum stress activation in VICs. The HDAC6 inhibition-induced osteogenic pathway was mediated by endoplasmic reticulum stress/ATF4 pathway as indicated by tauroursodeoxycholic acid pretreatment or ATF4 silencing. Finally, alizarin red staining showed that HDAC6 inhibition promoted osteoblastic differentiation of VICs, which could be suppressed by tauroursodeoxycholic acid.Conclusions: HDAC6 inhibition promotes AoV calcification via an endoplasmic reticulum stress/ATF4-mediated osteogenic pathway. HDAC6 may be a novel target for AoV calcification prevention and treatment.

miR-214 Attenuates Aortic Valve Calcification by Regulating Osteogenic Differentiation of Valvular Interstitial Cells

“…26 Recently, ATF4 has been reported to be upregulated in calcified aortic tissues. 27,28 In this paper, we found that downregulation of ATF4 expression inhibited mineralization of VICs, indicating the functional importance of ATF4 in aortic valve calcification. The mechanism of ATF4 in regulating osteogenesis may be as follows: (1) ATF4 can directly regulate the expression of its downstream proteins, including OCN and RANKL.…”

HDAC6 Regulates the Fusion of Autophagosome and Lysosome to Involve in Odontoblast Differentiation

“…HDAC6 is a component of the signaling pathway that regulates cell morphology and maturation (Destaing et al, 2005). Recently, HDAC6 has been shown to be involved in osteoblast differentiation in several osteoblastic cell lines (Ozaki et al, 2013;Wang et al, 2020) and valvular interstitial cells (Fu et al, 2019). However, there has been limited investigation FIGURE 5 | HDAC6 affects the fusion of autophagosomes and lysosomes during odontoblast differentiation.…”

Commentary: Aortic valve calcification: A new story with a twist?

“…8 The interest in AVC research is increasing exponentially during the last decade, 1 and several osteogenic pathways leading to aortic valve calcification have been identified. 10 Most of these studies were conducted in vitro or using an animal model. Although the possible clinical implications of such molecular research are not entirely clear, with the rapid advancement of modern technology, it might be possible to apply regenerative strategy using novel molecular pathways to prevent the calcification and degeneration of valvular tissue.…”