The hydrology and geochemistry of a saline spring fen peatland in the Athabasca oil sands region of Alberta

Due to the nature of the regional geology and the bitumen extraction process, the post-mined landscape of Canada’s oil sands region will have a much higher concentration of dissolved salts than it did prior to mining. As a result, naturally saline wetlands may constitute appropriate reclamation targets and knowledge of saline wetland hydrology can provide important clues to their form and function. Furthermore, the presence of saline discharge features in the Athabasca oil sands region (AOSR) provides an opportunity to study more closely the nature of groundwater flow in a region of considerable hydrogeologic complexity, including the origin and flow history of brines and the link between springs, subsurface wastewater containment and surface water quality. A low-flow saline-spring fen peatland located adjacent to a proposed in-situ oil extraction facility was examined south of the oil sands hub of Fort McMurray, Alberta. Hydrologically disconnected from underlying Devonian deposits that are a typical source of salinity, a saline groundwater plume originating from a Lower Cretaceous aquifer (the Grand Rapids Formation) was identified as a likely source for the accumulation of Na+ (mean of 6,949 mg L-1) and Cl- (mean of 13,766 mg L-1) in fen groundwater. Considerable spatial variability in ground and surface water salinity was observed, with the concentration of dissolved salts decreasing by an order of magnitude in the direction of flow. A sharp decrease in near-surface salinity was found along the entire perimeter between the fen and adjacent freshwater wetlands. Patterns in deep groundwater flux were difficult to interpret due to possible inaccuracies associated with the piezometer network (e.g., time-lag errors in low hydraulic conductivity substrates), and rates of groundwater input were estimated to be small (< 1 mm over a season) due to the low conductivity of the underlying mineral till (5.5x10-7 cm s-1). Water table dynamics were exaggerated in response to wetting and drying for both study seasons and the fen’s small subsurface storage capacity was readily exceeded under periods of sustained rainfall. The large pond network functioned as an effective transmitter of surface water during periods of high water table but was a sink of groundwater during dry periods due to high rates of evaporation. Despite flooding conditions observed in 2012, groundwater exchange between the fen and adjacent wetlands was low and the rough microtopography worked to detain surface waters and restrict runoff in the fen’s lower reaches. Together these mechanisms worked to isolate the saline fen and restrict the flux of saline waters into the surrounding landscape. Elevated concentrations of dissolved salts in nearby wetland and river systems indicates that influence of saline discharge is not solely restricted to the region’s major river systems. The flux of salt from saline wetlands may play an important role in the overall water quality of groundwater and receiving water bodies (e.g., nearby river systems). The geochemical signature of fen groundwater points to halite as a source of salinity, as indicated by Cl-/Br- ratios in excess of 7,000. This is in contrast to what has been observed for regional formation brines that are typically related to evaporated seawater. Isotopic evidence and relatively low salinities compared to springs in the Wood Buffalo region suggests that fen discharge water may be significantly diluted as a result of mixing with freshwater sources. The contribution of evaporite to discharge water may be coming from somewhere deeper and further south in the basin. This has important implications for the disposal of wastewater by deep well injection, as disposal zones may be hydrologically linked to near-surface aquifers and discharge features well beyond the immediate production and storage area

Kallistatin limits abdominal aortic aneurysm by attenuating generation of reactive oxygen species and apoptosis

Inflammation, vascular smooth muscle cell apoptosis and oxidative stress are believed to play important roles in abdominal aortic aneurysm (AAA) pathogenesis. Human kallistatin (KAL; gene SERPINA4) is a serine proteinase inhibitor previously shown to inhibit inflammation, apoptosis and oxidative stress. The aim of this study was to investigate the role of KAL in AAA through studies in experimental mouse models and patients. Serum KAL concentration was negatively associated with the diagnosis and growth of human AAA. Transgenic overexpression of the human KAL gene (KS-Tg) or administration of recombinant human KAL (rhKAL) inhibited AAA in the calcium phosphate (CaPO4) and subcutaneous angiotensin II (AngII) infusion mouse models. Upregulation of KAL in both models resulted in reduction in the severity of aortic elastin degradation, reduced markers of oxidative stress and less vascular smooth muscle apoptosis within the aorta. Administration of rhKAL to vascular smooth muscle cells incubated in the presence of AngII or in human AAA thrombus-conditioned media reduced apoptosis and downregulated markers of oxidative stress. These effects of KAL were associated with upregulation of Sirtuin 1 activity within the aortas of both KS-Tg mice and rodents receiving rhKAL. These results suggest KAL-Sirtuin 1 signalling limits aortic wall remodelling and aneurysm development through reductions in oxidative stress and vascular smooth muscle cell apoptosis. Upregulating KAL may be a novel therapeutic strategy for AAA. © 2021, The Author(s)

Blockade of mini-TrpRS for treatment of diabetic foot syndrome

Diabetic foot syndrome demonstrates wound chronicity due to impaired tissue perfusion in lower limbs. Previous studies showed interferon-gamma (IFN-γ), a central inflammatory mediator in diabetic foot syndrome, to induce the truncated form of tryptophanyl-tRNA synthetase (mini-TrpRS) that has strong angiostatic properties. Recently we reported that mini-TrpRS signalling could be blocked in the presence of IFN-γ with D-tryptophan in vitro. Here we discuss the IFN-γ/mini-TrpRS axis in the pathology of diabetic foot syndrome and emerging therapeutic options

Upregulation of arylsulfatase B in carotid atherosclerosis is associated with symptoms of cerebral embolization

The aim of this study was to identify genes for which the expression within carotid atherosclerosis was reproducibly associated with the symptoms of cerebral embolization. Two publically available microarray datasets E-MEXP-2257 and GSE21545 were analysed using GeneSpring 11.5. The two datasets utilized a total of 22 and 126 carotid atherosclerosis samples, obtained from patients with and without symptoms of cerebral embolization, respectively. To assess whether the findings were reproducible we analysed carotid atherosclerosis samples from another 8 patients with and 7 patients without symptoms of cerebral embolization using real-time PCR. In vitro studies using VSMC were performed to assess the functional relevance of one of the validated genes. We identified 1624 and 135 differentially expressed genes within carotid atherosclerosis samples of symptomatic compared to asymptomatic patients using the E-MEXP-2257 and GSE21545 datasets, respectively (≥1.15-absolute fold-change, P < 0.05). Only 7 differentially expressed genes or 0.4% (7/1,752) were consistent between the datasets. We validated the differential expression of ARSB which was upregulated 1.15-fold (P = 0.029) in atherosclerosis from symptomatic patients. In vitro incubation of VSMCs with the ARSB inhibitor L-ascorbic acid resulted in marked upregulation of SIRT1 and AMPK. This study suggests that ARSB may represent a novel target to limit carotid embolization

Kallikrein-1 blockade inhibits aortic expansion in a mouse model and reduces prostaglandin E2 secretion from human aortic aneurysm explants

Background: Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. The kinin B2 receptor agonist, bradykinin, has been implicated in AAA pathogenesis through promoting inflammation. Bradykinin is generated from high- and low-molecular-weight kininogen by the serine protease kallikrein-1. The aims of this study were first to examine the effect of neutralizing kallikrein-1 on AAA development in a mouse model and second to test how blocking kallikrein-1 affected cyclooxygenase-2 and prostaglandin E2 in human AAA explants. Methods and Results: Neutralization of kallikrein-1 in apolipoprotein E-deficient (ApoE-/-) mice via administration of a blocking antibody inhibited suprarenal aorta expansion in response to angiotensin (Ang) II infusion. Kallikrein-1 neutralization decreased suprarenal aorta concentrations of bradykinin and prostaglandin E2 and reduced cyclooxygenase-2 activity. Kallikrein-1 neutralization also decreased protein kinase B and extracellular signal-regulated kinase 1/2 phosphorylation and reduced levels of active matrix metalloproteinase 2 and matrix metalloproteinase 9. Kallikrein-1 blocking antibody reduced levels of cyclooxygenase-2 and secretion of prostaglandin E2 and active matrix metalloproteinase 2 and matrix metalloproteinase 9 from human AAA explants and vascular smooth muscle cells exposed to activated neutrophils. Conclusions: These findings suggest that kallikrein-1 neutralization could be a treatment target for AAA

Urocortin 2 inhibits human aortic smooth muscle cell proliferation via corticotrophin releasing hormone receptor-2 in abdominal aortic aneurysm

Introduction: A key feature of abdominal aortic aneurysm is the loss of proliferation and paucity of vascular smooth muscle cells, the major cells within the aortic tunica media. It has been suggested that urocortin 2 (UCN2), a selective ligand for corticotrophin releasing factor receptor 2 (CRFR2) may play a beneficial role in various cardiovascular diseases. However, the role of this peptide in abdominal aortic aneurysm has not been studied in detail. Here we assessed the hypothesis that urocortin 2 promotes an aneurysm phenotype in human aortic smooth muscles in vitro via CRFR2. Experimental Procedure: We assessed the release of UCN2 from explants of human tissue biopsies in vitro (Aortic aneurysm thrombus, n = 14; aortic aneurysm body, n = 11; femoral atheroma control, n = 6) using ELISA. We investigated the effect of incubating human aortic smooth muscle cells with recombinant UCN2 or aneurysm thrombus explants secretions at a UCN2 dose of 0, 10 and 100 nM for 24 and 48 hours (n = 6 per group x 3 experiments). Cell proliferation was determined by the alamarBlue® cell viability reagent. Results were analyzed and presented as mean ± SEM relative to the control. We also investigated the impact of blocking CRFR2 on UCN2 induced changes on these cells. Results: Secretion of UCN2 was significantly higher from aneurysm thrombus (n = 14, p = 0.0020) and aneurysm body (n = 11, p = 0.0104) compared to femoral atheroma. Human aortic smooth muscle cells proliferation was dose dependently inhibited by recombinant UCN2 (p = 0.0172) and aortic aneurysm thrombus conditioned medium (p = 0.0273) after 24 hours. This effect of recombinant UCN2 was abrogated significantly by prior incubation with the CRFR2 blocker Astressin-2B (p = 0.0043). Similar effects were seen on incubating cells for 48 hours. Conclusion: UCN2 is released in high concentrations by aortic aneurysm thrombus. UCN2 inhibits aortic vascular smooth muscle cell proliferation in vitro via CRFR2. This effect may be relevant to the pathogenesis of abdominal aortic aneurysm

Urocortin 2 inhibits human aortic smooth muscle cell proliferation via corticotrophin releasing hormone receptor-2 in abdominal aortic aneurysm

Introduction: A key feature of abdominal aortic aneurysm is the loss of proliferation and paucity of vascular smooth muscle cells, the major cells within the aortic tunica media. It has been suggested that urocortin 2 (UCN2), a selective ligand for corticotrophin releasing factor receptor 2 (CRFR2) may play a beneficial role in various cardiovascular diseases. However, the role of this peptide in abdominal aortic aneurysm has not been studied in detail. Here we assessed the hypothesis that urocortin 2 promotes an aneurysm phenotype in human aortic smooth muscles in vitro via CRFR2. Experimental Procedure: We assessed the release of UCN2 from explants of human tissue biopsies in vitro (Aortic aneurysm thrombus, n = 14; aortic aneurysm body, n = 11; femoral atheroma control, n = 6) using ELISA. We investigated the effect of incubating human aortic smooth muscle cells with recombinant UCN2 or aneurysm thrombus explants secretions at a UCN2 dose of 0, 10 and 100 nM for 24 and 48 hours (n = 6 per group x 3 experiments). Cell proliferation was determined by the alamarBlue® cell viability reagent. Results were analyzed and presented as mean ± SEM relative to the control. We also investigated the impact of blocking CRFR2 on UCN2 induced changes on these cells. Results: Secretion of UCN2 was significantly higher from aneurysm thrombus (n = 14, p = 0.0020) and aneurysm body (n = 11, p = 0.0104) compared to femoral atheroma. Human aortic smooth muscle cells proliferation was dose dependently inhibited by recombinant UCN2 (p = 0.0172) and aortic aneurysm thrombus conditioned medium (p = 0.0273) after 24 hours. This effect of recombinant UCN2 was abrogated significantly by prior incubation with the CRFR2 blocker Astressin-2B (p = 0.0043). Similar effects were seen on incubating cells for 48 hours. Conclusion: UCN2 is released in high concentrations by aortic aneurysm thrombus. UCN2 inhibits aortic vascular smooth muscle cell proliferation in vitro via CRFR2. This effect may be relevant to the pathogenesis of abdominal aortic aneurysm

Angiopoietin-2 attenuates angiotensin II-induced aortic aneurysm and atherosclerosis in apolipoprotein E-deficient mice

Angiogenesis and inflammation are implicated in aortic aneurysm and atherosclerosis and regulated by angiopoietin-2 (Angpt2). The effect of Angpt2 administration on experimental aortic aneurysm and atherosclerosis was examined. Six-month-old male apolipoprotein E deficient (ApoE⁻/⁻) mice were infused with angiotensin II (AngII) and administered subcutaneous human Fc-protein (control) or recombinant Angpt2 (rAngpt2) over 14 days. Administration of rAngpt2 significantly inhibited AngII-induced aortic dilatation and rupture of the suprarenal aorta (SRA), and development of atherosclerosis within the aortic arch. These effects were blood pressure and plasma lipoprotein independent and associated with Tie2 activation and down-regulation of monocyte chemotactic protein-1 (MCP-1) within the SRA. Plasma concentrations of MCP-1 and interleukin-6 were significantly lower in mice receiving rAngpt2. Immunostaining for the monocyte/macrophage marker MOMA-2 and the angiogenesis marker CD31 within the SRA were less in mice receiving rAngpt2 than controls. The percentage of inflammatory (Ly6Cʰⁱ) monocytes within the bone marrow was increased while that in peripheral blood was decreased by rAngpt2 administration. In conclusion, administration of rAngpt2 attenuated angiotensin II-induced aortic aneurysm and atherosclerosis in ApoE⁻/⁻ mice associated with reduced aortic inflammation and angiogenesis. Up-regulation of Angpt2 may have potential therapeutic value in patients with aortic aneurysm and atherosclerosis

Factor XII blockade inhibits aortic dilatation in angiotensin II-infused apolipoprotein E-deficient mice

Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. Chronic inflammation and excessive matrix remodelling are considered important in AAA pathogenesis. Kinins are bioactive peptides important in regulating inflammation. Stimulation of the kinin B2 receptor has been previously reported to promote AAA development and rupture in a mouse model. The endogenous B2 receptor agonist, bradykinin, is generated from the kallikrein-kinin system following activation of plasma kallikrein by Factor XII (FXII). In the current study whole-body FXII deletion, or neutralisation of activated FXII (FXIIa), inhibited expansion of the suprarenal aorta (SRA) of apolipoprotein E-deficient mice in response to angiotensin II (AngII) infusion. FXII deficiency or FXIIa neutralisation led to decreased aortic tumor necrosis factor-alpha-converting enzyme (TACE/a disintegrin and metalloproteinase-17 (aka tumor necrosis factor-alpha-converting enzyme) (ADAM-17)) activity, plasma kallikrein concentration, and epithelial growth factor receptor (EGFR) phosphorylation compared with controls. FXII deficiency or neutralisation also reduced Akt1 and Erk1/2 phosphorylation and decreased expression and levels of active matrix metalloproteinase (Mmp)-2 and Mmp-9. The findings suggest that FXII, kallikrein, ADAM-17, and EGFR are important molecular mediators by which AngII induces aneurysm in apolipoprotein E-deficient mice. This could be a novel pathway to target in the design of drugs to limit AAA progression