iRAGE as a novel carboxymethylated peptide that prevents advanced glycation end product-induced apoptosis and endoplasmic reticulum stress in vascular smooth muscle cells

Maltais, Jean-Sébastien; Simard, Elie; Froehlich, Ulrike; Denault, Jean‐Bernard; Gendron, Louis; Grandbois, Michel

doi:10.1016/j.phrs.2015.12.015

Cited by 11 publications

(5 citation statements)

References 81 publications

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“…In the aorta of CKD patients, apoptotic cell death was observed in vascular calcified area [ 43 ]. In diabetes or hyperglycemic condition, VSMCs exhibited significantly increased rates of proliferation, apoptosis, and migration, and decreased expression of contractile regulating proteins as well as abnormal cellular morphology, suggesting that normal vascular structure and function are impaired [ 44 , 45 , 46 , 47 , 48 ]. Therefore, prevention of AGE generation or AGE-RAGE interaction can be a therapeutic target of the progression of arteriosclerosis including vascular calcification [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

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Advanced Glycation End-Products Induce Apoptosis of Vascular Smooth Muscle Cells: A Mechanism for Vascular Calcification

Koike

Yano

Tanaka

et al. 2016

IJMS

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Vascular calcification, especially medial artery calcification, is associated with cardiovascular death in patients with diabetes mellitus and chronic kidney disease (CKD). To determine the underlying mechanism of vascular calcification, we have demonstrated in our previous report that advanced glycation end-products (AGEs) stimulated calcium deposition in vascular smooth muscle cells (VSMCs) through excessive oxidative stress and phenotypic transition into osteoblastic cells. Since AGEs can induce apoptosis, in this study we investigated its role on VSMC apoptosis, focusing mainly on the underlying mechanisms. A rat VSMC line (A7r5) was cultured, and treated with glycolaldehyde-derived AGE-bovine serum albumin (AGE3-BSA). Apoptotic cells were identified by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. To quantify apoptosis, an enzyme-linked immunosorbent assay (ELISA) for histone-complexed DNA fragments was employed. Real-time PCR was performed to determine the mRNA levels. Treatment of A7r5 cells with AGE3-BSA from 100 µg/mL concentration markedly increased apoptosis, which was suppressed by Nox inhibitors. AGE3-BSA significantly increased the mRNA expression of NAD(P)H oxidase components including Nox4 and p22phox, and these findings were confirmed by protein levels using immunofluorescence. Dihydroethidisum assay showed that compared with cBSA, AGE3-BSA increased reactive oxygen species level in A7r5 cells. Furthermore, AGE3-induced apoptosis was significantly inhibited by siRNA-mediated knockdown of Nox4 or p22phox. Double knockdown of Nox4 and p22phox showed a similar inhibitory effect on apoptosis as single gene silencing. Thus, our results demonstrated that NAD(P)H oxidase-derived oxidative stress are involved in AGEs-induced apoptosis of VSMCs. These findings might be important to understand the pathogenesis of vascular calcification in diabetes and CKD.

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Section: Discussionmentioning

confidence: 99%

“…Therefore, prevention of AGE generation or AGE-RAGE interaction can be a therapeutic target of the progression of arteriosclerosis including vascular calcification [ 13 ]. In addition, a very recent study has shown that AGE-induced VSMC apoptosis and ER stress are augmented by treatment with a novel carboxymethylated peptide [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Advanced Glycation End-Products Induce Apoptosis of Vascular Smooth Muscle Cells: A Mechanism for Vascular Calcification

Koike

Yano

Tanaka

et al. 2016

IJMS

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“…The RAGE-induced stimulation of NFkB activity promotes VSMC apoptosis. Induction of endoplasmic reticulum (ER) stress by RAGE activation has a key role in this process [ 77 ] via the HuR-dependent up-regulation of caspase-9 and Bcl-2 family proteins [ 78 ].…”

Section: The Impact Of Uremic Toxins On Vsmc Functionmentioning

confidence: 99%

The Impact of Uremic Toxins on Vascular Smooth Muscle Cell Function

Hénaut

Mary

Chillon

et al. 2018

Toxins

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Chronic kidney disease (CKD) is associated with profound vascular remodeling, which accelerates the progression of cardiovascular disease. This remodeling is characterized by intimal hyperplasia, accelerated atherosclerosis, excessive vascular calcification, and vascular stiffness. Vascular smooth muscle cell (VSMC) dysfunction has a key role in the remodeling process. Under uremic conditions, VSMCs can switch from a contractile phenotype to a synthetic phenotype, and undergo abnormal proliferation, migration, senescence, apoptosis, and calcification. A growing body of data from experiments in vitro and animal models suggests that uremic toxins (such as inorganic phosphate, indoxyl sulfate and advanced-glycation end products) may directly impact the VSMCs’ physiological functions. Chronic, low-grade inflammation and oxidative stress—hallmarks of CKD—are also strong inducers of VSMC dysfunction. Here, we review current knowledge about the impact of uremic toxins on VSMC function in CKD, and the consequences for pathological vascular remodeling.

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“…Stress and various stimuli can induce perturbations of the endoplasmic reticulum, which results in the accumulation of misfolded and unfolded proteins and the resultant pathologic consequences of apoptosis ( 16 ). Likewise, increasing evidence has elucidated the contribution of endoplasmic reticulum stress in the development of vascular calcification in pathologic conditions with pro-calcifying stimuli, such as high glucose in type 2 diabetes mellitus ( 17 ), chronic kidney diseases ( 18 ), and atherosclerosis ( 19 ). The endoplasmic reticulum stress-induced vascular calcification is known to be mediated by several molecules, such as activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) ( 20 21 ).…”

Section: Current View Of the Mechanisms Of Vascular Calcification: Osmentioning

confidence: 99%

New Aspects of Vascular Calcification: Histone Deacetylases and Beyond

2017

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Vascular calcification is a pathologic phenomenon in which calcium phosphate is ectopically deposited in the arteries. Previously, calcification was considered to be a passive process in response to metabolic diseases, vascular or valvular diseases, or even aging. However, now calcification is recognized as a highly-regulated consequence, like bone formation, and many clinical trials have been carried out to elucidate the correlation between vascular calcification and cardiovascular events and mortality. As a result, vascular calcification has been implicated as an independent risk factor in cardiovascular diseases. Many molecules are now known to be actively associated with this process. Recently, our laboratory found that posttranslational modification of histone deacetylase (HDAC) 1 is actively involved in the development of vascular calcification. In addition, we found that modulation of the activity of HDAC as well as its protein stability by MDM2, an HDAC1-E3 ligase, may be a therapeutic target in vascular calcification. In the present review, we overview the pathomechanism of vascular calcification and the involvement of posttranslational modification of epigenetic regulators.

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iRAGE as a novel carboxymethylated peptide that prevents advanced glycation end product-induced apoptosis and endoplasmic reticulum stress in vascular smooth muscle cells

Cited by 11 publications

References 81 publications

Advanced Glycation End-Products Induce Apoptosis of Vascular Smooth Muscle Cells: A Mechanism for Vascular Calcification

Advanced Glycation End-Products Induce Apoptosis of Vascular Smooth Muscle Cells: A Mechanism for Vascular Calcification

The Impact of Uremic Toxins on Vascular Smooth Muscle Cell Function

New Aspects of Vascular Calcification: Histone Deacetylases and Beyond

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