Endoplasmic Reticulum Stress Mediates Vascular Smooth Muscle Cell Calcification via Increased Release of Grp78 (Glucose-Regulated Protein, 78 kDa)-Loaded Extracellular Vesicles

Furmanik, Malgorzata; Gorp, Rick van; Whitehead, Meredith; Ahmad, Shahbaz; Bordoloi, Jayanta; Kapustin, Alexander; Schurgers, Leon J.; Shanahan, Catherine M.

doi:10.1161/atvbaha.120.315506

Cited by 66 publications

(58 citation statements)

References 75 publications

(34 reference statements)

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“…VKA treat-ment decreases the carboxylation and secretion of protein S, a coagulation inhibitor also synthesised by hVSMC and hEC [22,23]. Furthermore, VKAs induce hVSMC calcification via endoplasmic reticulum stress, a process independent of Gla protein activation [24]. The precise role of how the coagulation system is involved in CUA development is, to date, unclear.…”

Section: Discussionmentioning

confidence: 99%

Hepatic and Vascular Vitamin K Status in Patients with High Cardiovascular Risk

et al. 2021

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Vitamin K dependent proteins (VKDP), such as hepatic coagulation factors and vascular matrix Gla protein (MGP), play key roles in maintaining physiological functions. Vitamin K deficiency results in inactive VKDP and is strongly linked to vascular calcification (VC), one of the major risk factors for cardiovascular morbidity and mortality. In this study we investigated how two vitamin K surrogate markers, dephosphorylated-undercarboxylated MGP (dp-ucMGP) and protein induced by vitamin K absence II (PIVKA-II), reflect vitamin K status in patients on hemodialysis or with calcific uremic arteriolopathy (CUA) and patients with atrial fibrillation or aortic valve stenosis. Through inter- and intra-cohort comparisons, we assessed the influence of vitamin K antagonist (VKA) use, vitamin K supplementation and disease etiology on vitamin K status, as well as the correlation between both markers. Overall, VKA therapy was associated with 8.5-fold higher PIVKA-II (0.25 to 2.03 AU/mL) and 3-fold higher dp-ucMGP (843 to 2642 pM) levels. In the absence of VKA use, non-renal patients with established VC have dp-ucMGP levels similar to controls (460 vs. 380 pM), while in HD and CUA patients, levels were strongly elevated (977 pM). Vitamin K supplementation significantly reduced dp-ucMGP levels within 12 months (440 to 221 pM). Overall, PIVKA-II and dp-ucMGP showed only weak correlation (r2 ≤ 0.26) and distinct distribution pattern in renal and non-renal patients. In conclusion, VKA use exacerbated vitamin K deficiency across all etiologies, while vitamin K supplementation resulted in a vascular VKDP status better than that of the general population. Weak correlation of vitamin K biomarkers calls for thoughtful selection lead by the research question. Vitamin K status in non-renal deficient patients was not anomalous and may question the role of vitamin K deficiency in the pathogenesis of VC in these patients.

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Section: Discussionmentioning

confidence: 99%

Hepatic and Vascular Vitamin K Status in Patients with High Cardiovascular Risk

et al. 2021

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“…The expression of exosome/sEVs markers, CD63, and annexin A2 were significantly increased in the coronary arterial wall of Mcoln1 −/− mice (Bhat et al, 2020b). Endoplasmic reticulum (ER) stress induces calcification of VSMCs in vitro and modifies VSMCs phenotype by increasing the release of Grp78-loaded calcifying EVs (Furmanik et al, 2021).…”

Section: The Regulator Controlling Matrix Vesicles Secretionmentioning

confidence: 99%

Matrix Vesicles as a Therapeutic Target for Vascular Calcification

Zhang

et al. 2022

Front. Cell Dev. Biol.

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Vascular calcification (VC) is linked to an increased risk of heart disease, stroke, and atherosclerotic plaque rupture. It is a cell-active process regulated by vascular cells rather than pure passive calcium (Ca) deposition. In recent years, extracellular vesicles (EVs) have attracted extensive attention because of their essential role in the process of VC. Matrix vesicles (MVs), one type of EVs, are especially critical in extracellular matrix mineralization and the early stages of the development of VC. Vascular smooth muscle cells (VSMCs) have the potential to undergo phenotypic transformation and to serve as a nucleation site for hydroxyapatite crystals upon extracellular stimulation. However, it is not clear what underlying mechanism that MVs drive the VSMCs phenotype switching and to result in calcification. This article aims to review the detailed role of MVs in the progression of VC and compare the difference with other major drivers of calcification, including aging, uremia, mechanical stress, oxidative stress, and inflammation. We will also bring attention to the novel findings in the isolation and characterization of MVs, and the therapeutic application of MVs in VC.

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“…Additionally, endoplasmic reticulum stress in VSMC induces the release of EV rich in glucose-regulated protein, 78 kDa (GRP78), which deposition in the extracellular matrix promotes calcification, and this process was further stimulated by the anticoagulant warfarin [80]. Moreover, VSMC with a synthetic phenotype promote atherosclerotic calcification by releasing EV with the calcifying protein tissue nonspecific alkaline phosphatase (TNAP), in a mechanism mediated by sortilin phosphorylation [81].…”

Section: Plaque Calcificationmentioning

confidence: 99%

Extracellular vesicles in atherothrombosis and cardiovascular disease: Friends and foes

et al. 2021

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Extracellular vesicles (EV, exosomes and microvesicles -MV-) are 30-1000 nm particles surrounded by a phospholipid bilayer membrane that are released from almost all cell types through several pathways. EV encapsulate bioactive molecules, and the molecular cargo is determined by the trigger stimulating its release, reflecting its cell origin and biological functions.This review is primarily focused on the latest evidence of the roles of EV, released from cells involved in the different stages of atherothrombosis. The potential translation of this information to the clinical arena is also discussed.EV can have both pro-and anti-atherothrombotic effects depending on several factors, such as the type of vesicle (MV/exosome), its molecular cargo, its cell of origin, and the context in which are generated, i.e., the stimulus triggering its release. In fact, EV actively participate in every step of atherosclerosis onset and progression, and also in thrombus formation leading to a major adverse cardiovascular event. Moreover, EV have a determinant role in fibrous cap stability, thus determining the propensity of the plaque to rupture. On the other hand, and again, conditioned by the context and stimulus instigating its secretion, some EV may have protective biological functions, perhaps as a compensatory mechanism or even with reparative or regenerative potential. Therefore, the study of the implication of EV in atherothrombosis might be of relevance to unveil new therapeutic targets, vectors and biomarkers of cardiovascular disease (CVD).

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Endoplasmic Reticulum Stress Mediates Vascular Smooth Muscle Cell Calcification via Increased Release of Grp78 (Glucose-Regulated Protein, 78 kDa)-Loaded Extracellular Vesicles

Cited by 66 publications

References 75 publications

Hepatic and Vascular Vitamin K Status in Patients with High Cardiovascular Risk

Hepatic and Vascular Vitamin K Status in Patients with High Cardiovascular Risk

Matrix Vesicles as a Therapeutic Target for Vascular Calcification

Extracellular vesicles in atherothrombosis and cardiovascular disease: Friends and foes

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