Enhanced endoplasmic reticulum and mitochondrial stress in abdominal aortic aneurysm

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.

Role of the Scavenger Receptor CD36 in Accelerated Diabetic Atherosclerosis

“…Plasma was frozen in aliquots at –80 °C promptly after separation. Absolute quantification of 7-ketocholesterol (7-KC) was performed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) with atmospheric pressure chemical ionization (APCI) interface (UHPLC-(+)APCI-MS/MS) in the Centre for Omic Sciences (Reus, Tarragona, Spain), as previously described [ 63 ].…”

Recent progress in the LC–MS/MS analysis of oxidative stress biomarkers

“…This method was successfully applied to further investigate the Niemann‐Pick C1 and C2 disease [182,183], but recently, also to examine the role of these compounds in the presence of OS in patients with type 1 and type 2 diabetes, where it seems that both 7‐KC and cholestane‐3β,5α,6β‐triol may be used as sensitive biomarkers for monitoring OS in diabetes patients [184]. On the other hand, several oxysterols (24‐OHCh, 25‐OHCh, 27‐OHCh, 7α‐OHCh, 7β‐OHCh, and 7‐KC) were examined in plasma of patients with an abdominal aortic aneurysm, using two previously described UPLC–MS/MS methods [185]. Two different extraction methods were used for the quantification of free oxysterols (7‐KC and 27‐OHCh) and the quantification of the total oxysterols.…”

“…In addition, oxysterols are also involved in the pathophysiology of cardiovascular diseases, and therefore, the assumption is that the oxysterol levels might be altered in the plasma of AAA patients as well. Levels of free 7‐KC and other oxysterols (24‐OHCh, 25‐OHCh, 27‐OHCh, 7α‐OHCh, and 7β‐OHCh) were measured in the plasma of 94 AAA patients and 47 healthy controls [185]. Two extraction methods were developed and validated for (1) the quantification of 7‐KC and 27‐OHCh, using protein precipitation [186] and (2) the quantification of total oxysterols introducing a saponification step, followed by SPE [187,188] (Table 2).…”

Photobiomodulation and estrogen stabilize mitochondrial membrane potential in angiotensin–II challenged porcine aortic smooth muscle cells

“…In recent years, considerable evidence has accumulated pointing to the profound effects of disorders of mitochondrial function on various aspects of cardiovascular integrity [24,25] including AAA [26,27]. Ang-II has been shown to reduce mitochondrial membrane potential (MitMP) in vascular SMCs leading to reduced generation of ATP necessary for maintenance of essential cellular processes including extracellular matrix synthesis [28].…”