scholarly journals Enhanced endoplasmic reticulum and mitochondrial stress in abdominal aortic aneurysm

2019 ◽  
Vol 133 (13) ◽  
pp. 1421-1438 ◽  
Author(s):  
Miquel Navas-Madroñal ◽  
Cristina Rodriguez ◽  
Modar Kassan ◽  
Joan Fité ◽  
José R. Escudero ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Er Stress ◽  
Mitochondrial Biogenesis ◽  
Atmospheric Pressure Chemical Ionization ◽  
Vascular Wall ◽  
Protein Levels ◽  
Abdominal Aortic ◽  
Healthy Donors

Abstract Abdominal aortic aneurysm (AAA) is a degenerative vascular disease with a complex aetiology that remains to be fully elucidated. Clinical management of AAA is limited to surgical repair, while an effective pharmacotherapy is still awaited. Endoplasmic reticulum (ER) stress and mitochondrial dysfunction have been involved in the pathogenesis of cardiovascular diseases (CVDs), although their contribution to AAA development is uncertain. Therefore, we aimed to determine their implication in AAA and investigated the profile of oxysterols in plasma, specifically 7-ketocholesterol (7-KC), as an ER stress inducer. In the present study, we determined aortic ER stress activation in a large cohort of AAA patients compared with healthy donors. Higher gene expression of activating transcription factor (ATF) 6 (ATF6), IRE-1, X-binding protein 1 (XBP-1), C/EBP-homologous protein (CHOP), CRELD2 and suppressor/enhancer of Lin-12-like (SEL1L) and greater protein levels of active ATF6, active XBP1 and of the pro-apoptotic protein CHOP were detected in human aneurysmatic samples. This was accompanied by an exacerbated apoptosis, higher reactive oxygen species (ROS) production and by a reduction in mitochondrial biogenesis in the vascular wall of AAA. The quantification of oxysterols, performed by liquid chromatography-(atmospheric pressure chemical ionization (APCI))-mass spectrometry, showed that levels of 7-KC were significantly higher while those of 7α-hydroxycholesterol (HC), 24-HC and 27-HC were lower in AAA patients compared with healthy donors. Interestingly, the levels of 7-KC correlate with the expression of ER stress markers. Our results evidence an induction of ER stress in the vascular wall of AAA patients associated with an increase in circulating 7-KC levels and a reduction in mitochondrial biogenesis suggesting their implication in the pathophysiology of this disease.

Endoplasmic reticulum stress and mitochondrial biogenesis are potential therapeutic targets for abdominal aortic aneurysm

2019 ◽  
Vol 133 (19) ◽  
pp. 2023-2028 ◽  
Author(s):  
Masashi Miyao ◽  
Stephanie Cicalese ◽  
Hannah A. Cooper ◽  
Satoru Eguchi
Keyword(s):  
Endoplasmic Reticulum ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Er Stress ◽  
Mitochondrial Biogenesis ◽  
Underlying Mechanism ◽  
Causative Factor ◽  
Elevated Concentration ◽  
Future Directions ◽  
Abdominal Aortic

Abstract Endoplasmic reticulum (ER) and mitochondria are crucial organelles for cell homeostasis and alterations of these organelles have been implicated in cardiovascular disease. However, their roles in abdominal aortic aneurysm (AAA) pathogenesis remain largely unknown. In a recent issue of Clinical Science, Navas-Madronal et al. ((2019), 133(13), 1421–1438) reported that enhanced ER stress and dysregulation of mitochondrial biogenesis are associated with AAA pathogenesis in humans. The authors also proposed that disruption in oxysterols network such as an elevated concentration of 7-ketocholestyerol in plasma is a causative factor for AAA progression. Their findings highlight new insights into the underlying mechanism of AAA progression through ER stress and dysregulation of mitochondrial biogenesis. Here, we will discuss the background, significance of the study, and future directions.

Abstract 3718: MMP-12 Inhibitor Reduces Severity of ANGII-induced Aortic Abdominal Aneurysms in apoE−/− Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Dawn A Savio ◽  
Anita R Halpern ◽  
Yuchuan Wu ◽  
Wei Li ◽  
Joseph Sypek ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Vascular Wall ◽  
Inflammatory Disorder ◽  
Gene Markers ◽  
Genetic Ablation ◽  
Macrophage Recruitment ◽  
Aneurysm Formation ◽  
Abdominal Aortic

Abdominal aortic aneurysm (AAA) is an inflammatory disorder characterized by local connective tissue degradation, macrophage recruitment and infiltration leading to aortic dilation and rupture. Aneurysms of the abdominal aorta represent a significant cardiovascular risk for which inflammation plays an integral role in the defined pathology. Genetic ablation of metalloprotease-12 (MMP-12) eliminates metalloelastase activity and attenuates aneurysm formation in apoE−/− mice. In the current study, a selective MMP-12 inhibitor, WAY-644 was evaluated in the well-established murine model of ANGII-induced aneurysm formation. This inhibitor displays activity for murine MMP-12, IC50 = 6.3 nM by FRET analysis, with low crossreactivity for other MMPs (exception MMP-8), and has established in vivo efficacy in inflammation models. Coadministration of WAY-644 to hyperlipidemic apoE−/− mice during ANGII infusion (1.44 mg/kg) for 28d alters the severity of AngII-induced AAAs as measured by changes in abdominal aortic wet weights and typical AAA classification. As expected, plasma MMP-12 protease activity measured by FRET analysis was inhibited. RNA profiling of abdominal aortic aneurysm tissue characterizes ANGII-induced AAA expansion driven by macrophage infiltration, destructive MMP production and attenuation by MMP-12 inhibition. The transcription of a subset of proinflammatory genes activated with ANGII treatment was repressed by the inhibitor. These genes include quantitative markers of macrophage accumulation in the vessel wall, CD68, MCP1/CCL2, CCR2, MMP-12, and Csf1. Associated reductions in gene markers for inflammation and oxidative stress, ie., heme oxidase (HO), nitric oxide synthase (nos2), Ikbkb, and Stat3 also correlate with MMP-12 antagonism. These changes occur in the absence of lipid changes (TC or TG), or quantitative changes in aortic arch lesions in the ANGII-infused animals. The findings support a mechanism whereby MMP-12 metalloelastase inactivation reduces macrophage recruitment to aneurysmal lesion sites, to lessen activated-macrophage expression of proinflammatory cytokines that figure prominently in vascular wall destruction and the pathogenesis of AAAs.

scholarly journals Adipocyte in vascular wall can induce the rupture of abdominal aortic aneurysm

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Hirona Kugo ◽  
Nobuhiro Zaima ◽  
Hiroki Tanaka ◽  
Youhei Mouri ◽  
Kenichi Yanagimoto ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Vascular Wall ◽  
Abdominal Aortic

scholarly journals Ovariectomy increases the incidence and diameter of abdominal aortic aneurysm in a hypoperfusion-induced abdominal aortic aneurysm animal model

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Chie Miyamoto ◽  
Hirona Kugo ◽  
Keisuke Hashimoto ◽  
Tatsuya Moriyama ◽  
Nobuhiro Zaima
Keyword(s):  
Growth Rate ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Incidence Rate ◽  
Vascular Wall ◽  
Vascular Walls ◽  
Abdominal Aortic ◽  
Male Sex ◽  
Aneurysm Diameter ◽  
Metalloproteinase 9

AbstractAbdominal aortic aneurysm (AAA) is a vascular disease characterized by weakening of the vascular walls. Male sex is a risk factor for AAA, and peak AAA incidence occurs in men 10 years earlier than in women. However, the growth rate of AAA is faster in women, and women have a higher mortality due to AAA rupture. The mechanisms underlying sex-related differences in AAA remain unknown. Herein, we evaluated the effects of ovariectomy (OVX) on AAA in rats. Upon evaluation of the effects of OVX and AAA induction, AAA incidence rate and the aneurysm diameter increased in the OVX group. However, the histopathology in the developed AAA wall was not different between groups. When the effects of OVX on the vascular wall without AAA induction were evaluated, elastin and collagen levels were significantly decreased. Furthermore, the level of matrix metalloproteinase-9 significantly increased in the OVX group. According to our results, it is speculated that decreased levels of collagen and elastin fibers induced by OVX might be involved in increased incidence rate and diameter of AAA. Weakening of the vascular wall before the onset of AAA might be one reason for the faster rate of AAA growth in women.

scholarly journals Pathological Analysis of the Ruptured Vascular Wall of Hypoperfusion-induced Abdominal Aortic Aneurysm Animal Model

2017 ◽  
Vol 66 (5) ◽  
pp. 499-506 ◽  
Author(s):  
Hirona Kugo ◽  
Nobuhiro Zaima ◽  
Hiroki Tanaka ◽  
Keisuke Hashimoto ◽  
Chie Miyamoto ◽  
...  
Keyword(s):  
Animal Model ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Vascular Wall ◽  
Pathological Analysis ◽  
Abdominal Aortic

scholarly journals Increased PAI-1 in females compared with males is protective for abdominal aortic aneurysm formation in a rodent model

2012 ◽  
Vol 302 (7) ◽  
pp. H1378-H1386 ◽  
Author(s):  
Paul D. DiMusto ◽  
Guanyi Lu ◽  
Abhijit Ghosh ◽  
Karen J. Roelofs ◽  
Gang Su ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Serine Proteases ◽  
Protective Factor ◽  
Experimental Aneurysm ◽  
Male And Female ◽  
Protein Levels ◽  
Aneurysm Formation ◽  
Abdominal Aortic ◽  
Pai 1

The serine proteases, along with their inhibitor plasmin activator inhibitor-1 (PAI-1), have been shown to play a role in abdominal aortic aneurysm (AAA) formation. The aim of this study is to determine if PAI-1 may be a protective factor for AAA formation and partially responsible for the gender difference observed in AAAs. Male and female wild-type (WT) C57BL/6 and PAI-1−/−mice 8–12 wk of age underwent aortic perfusion with porcine pancreatic elastase. Animals were harvested 14 days following perfusion and analyzed for phenotype, PAI-1 protein levels, and matrix metalloproteinase (MMP)-9 and -2 activity. WT males had an average increase in aortic diameter of 80%, whereas females only increased 32% ( P < 0.001). PAI-1−/−males increased 204% and females 161%, significantly more than their WT counterparts ( P < 0.001). Western blot revealed 61% higher PAI-1 protein levels in the WT females compared with the WT males ( P = 0.01). Zymography revealed higher levels of pro-MMP-2 and active MMP-2 in the PAI-1−/−males and females compared with their WT counterparts. PAI-1−/−females had significantly higher serum plasmin levels compared with WT females ( P = 0.003). In conclusion, WT female mice are protected from aneurysm formation and have higher levels of PAI-1 compared with males during experimental aneurysm formation. Additionally, both male and female PAI-1−/−animals develop significantly larger aneurysms than WT animals, correlating with higher pro- and active MMP-2 levels. These findings suggest that PAI-1 is protective for aneurysm formation in the elastase model of AAA and plays a role in the gender differences seen in AAA formation.

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