Mechanism of Endoplasmic Reticulum Stress Pathway in the Osteogenic Phenotypic Transformation of Aortic Valve Interstitial Cells

Abstract

Background and PurposeCalcific Aortic Valve Disease (CAVD) is a crucial component of degenerative valvular disease in old age and with the increasing prevalence of the aging population. we hope that by modeling valvular osteogenesis and intervening with endoplasmic reticulum stress inhibitor TUDCA to observe the effect of endoplasmic reticulum stress on valve osteogenesisMethodsIn this study, rabbit heart valvular interstitial cells (VICs) were isolated and cultured. They treated with ox-LDL (Oxidized Low Density Lipoprotein) stimulation to establish a model of valvular osteogenic transformation. BMP2 (Bone Morphogenetic Protein 2), PERK (Protein kinase R-like endoplasmic reticulum kinase), CHOP (CCAAT/enhancer-binding protein homologous protein) and transcriptional regulatory factor ATF4 (Activating Transcription Factor 4 )were recorded after intervention with ER stress inhibitor TUDCA. The effects of er stress on valvular osteogenic transformation were analyzed.ResultAfter stimulation of VICs with ox-LDL, the expression levels of BMP2, PERK, CHOP, and ATF4 increased. However, TUDCA treatment can alleviate the increased expression levels of BMP2, PERK ATF4, and CHOP under ox-LDL stimulation to a certain extent.ConclusionThe endoplasmic reticulum stress signaling pathway is involved in ox-LDL-induced calcification of rabbit valve interstitial cells. Inhibition of endoplasmic reticulum stress using TUDCA can improve the progression of rabbit aortic valve calcification.

Tauroursodeoxycholic acid functions as a critical effector mediating insulin sensitization of metformin in obese mice

“…TUDCA improves insulin sensitivity and increases pancreatic β cell mass in obese humans or murine models of obesity and diabetes [ 20 , 21 ]. TUDCA can mitigate endoplasmic reticulum (ER) stress and restore the expression of unfolded protein response (UPR) mediators [ 22 ], and is involved in PI3K/AKT cascade signaling activation to inhibit apoptosis [ 23 , 24 ]. Both effects in turn reduce apoptosis of pancreatic β cells and maintain insulin secretion [ 25 ].…”

Overview on hydrogen sulfide-mediated suppression of vascular calcification and hemoglobin/heme-mediated vascular damage in atherosclerosis

“…Vascular SMCs (VSMCs) and valvular interstitial cells (VICs) are critical for maintaining the physiologic functions of the vasculature, and their osteo-chondrogenic transformation triggered by calcifying stimuli such as high plasma phosphate (Pi) [ 116 ], Lipoprotein(a) [ 117 ], or, lipid oxidation products including LDLox [ 118 , 119 ] play an etiologic role in atherosclerosis and CAVD development [ 120 ]. Atherosclerosis is commonly associated with intimal calcification, while medial calcification mainly occurs in chronic kidney disease [ 121 ] and diabetes mellitus [ 122 ]; both dramatically aggravate plaque development and progression.…”

Seasonal changes in endoplasmic reticulum stress and ovarian steroidogenesis in the muskrats (Ondatra zibethicus)

“…Numerous physiological and pathological processes, including excessive secretion requirement, damaged calcium homeostasis, changed lipid homeostasis, oxidative stress, and production of the mutant protein linked to disease all contribute to the induction of ERS ( 4 – 7 ). When ERS occurs, the three embranchments of the unfolded protein response (UPR) signaling are decoupled from glucose-regulated protein 78 (GRP78) and activated, which are protein kinase RNA (PKR)-like ER kinase (PERK), inositolrequiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6) ( 8 , 9 ). PERK phosphorylates eukaryotic initiation factor 2α (eIF-2α), which inhibits the entry of new proteins into the endoplasmic reticulum and attenuates translational initiation once activated.…”