Search: onr:"swepub:oai:lup.lub.lu.se:e2a29af4-d7d5-4c0a-931d-758c85efeb9b" >
Heme induces endopl...
Heme induces endoplasmic reticulum stress (Hier stress) in human aortic smooth muscle cells
-
- Gáll, Tamás (author)
- University of Debrecen
-
- Pethő, Dávid (author)
- University of Debrecen
-
- Nagy, Annamária (author)
- University of Debrecen
-
show more...
-
- Hendrik, Zoltán (author)
- University of Debrecen
-
- Méhes, Gábor (author)
- University of Debrecen
-
- Potor, László (author)
- University of Debrecen
-
- Gram, Magnus (author)
- Lund University,Lunds universitet,Antioxidationsmedicin,Forskargrupper vid Lunds universitet,Antioxidation medicine,Lund University Research Groups
-
- Åkerström, Bo (author)
- Lund University,Lunds universitet,Antioxidationsmedicin,Forskargrupper vid Lunds universitet,Antioxidation medicine,Lund University Research Groups
-
- Smith, Ann (author)
- University of Missouri-Kansas City
-
- Nagy, Péter (author)
- University of Debrecen
-
- Balla, György (author)
- University of Debrecen
-
- Balla, József (author)
- University of Debrecen
-
show less...
-
(creator_code:org_t)
- 2018-11-20
- 2018
- English.
-
In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 9:NOV
- Related links:
-
http://dx.doi.org/10... (free)
-
show more...
-
https://www.frontier...
-
https://lup.lub.lu.s...
-
https://doi.org/10.3...
-
show less...
Abstract
Subject headings
Close
- Accumulation of damaged or misfolded proteins resulted from oxidative protein modification induces endoplasmic reticulum (ER) stress by activating the pathways of unfolded protein response. In pathologic hemolytic conditions, extracellular free hemoglobin is submitted to rapid oxidation causing heme release. Resident cells of atherosclerotic lesions, after intraplaque hemorrhage, are exposed to heme leading to oxidative injury. Therefore, we raised the question whether heme can also provoke ER stress. Smooth muscle cells are one of the key players of atherogenesis; thus, human aortic smooth muscle cells (HAoSMCs) were selected as a model cell to reveal the possible link between heme and ER stress. Using immunoblotting, quantitative polymerase chain reaction and immunocytochemistry, we quantitated the markers of ER stress. These were: phosphorylated eIF2α, Activating transcription factor-4 (ATF4), DNA-damage-inducible transcript 3 (also known as C/EBP homology protein, termed CHOP), X-box binding protein-1 (XBP1), Activating transcription factor-6 (ATF6), GRP78 (glucose-regulated protein, 78kDa) and heme responsive genes heme oxygenase-1 and ferritin. In addition, immunohistochemistry was performed on human carotid artery specimens from patients who had undergone carotid endarterectomy. We demonstrate that heme increases the phosphorylation of eiF2α in HAoSMCs and the expression of ATF4. Heme also enhances the splicing of XBP1 and the proteolytic cleavage of ATF6. Consequently, there is up-regulation of target genes increasing both mRNA and protein levels of CHOP and GRP78. However, TGFβ and collagen type I decreased. When the heme binding proteins, alpha-1-microglobulin (A1M) and hemopexin (Hpx) are present in cell media, the ER stress provoked by heme is inhibited. ER stress pathways are also retarded by the antioxidant N-acetyl cysteine (NAC) indicating that reactive oxygen species are involved in heme-induced ER stress. Consistent with these findings, elevated expression of the ER stress marker GRP78 and CHOP were observed in smooth muscle cells of complicated lesions with hemorrhage compared to either atheromas or healthy arteries. In conclusion, heme triggers ER stress in a time- and dose-dependent manner in HAoSMCs. A1M and Hpx as well as NAC effectively hamper heme-induced ER stress, supporting their use as a potential therapeutic approach to reverse such a deleterious effects of heme toxicity.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Physiology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
Keyword
- Alpha-1-microglobulin
- Atherosclerosis
- Heme
- Heme induced endoplasmic reticulum stress
- Hemopexin
- Vascular smooth muscle cell
Publication and Content Type
- art (subject category)
- ref (subject category)
Find in a library
To the university's database
- By the author/editor
-
Gáll, Tamás
-
Pethő, Dávid
-
Nagy, Annamária
-
Hendrik, Zoltán
-
Méhes, Gábor
-
Potor, László
-
show more...
-
Gram, Magnus
-
Åkerström, Bo
-
Smith, Ann
-
Nagy, Péter
-
Balla, György
-
Balla, József
-
show less...
- About the subject
-
- MEDICAL AND HEALTH SCIENCES
-
MEDICAL AND HEAL ...
-
and Basic Medicine
-
and Physiology
-
- MEDICAL AND HEALTH SCIENCES
-
MEDICAL AND HEAL ...
-
and Clinical Medicin ...
-
and Cardiac and Card ...
- Articles in the publication
-
Frontiers in Phy ...
- By the university
-
Lund University