Esmolol reduces myocardial injury induced by resuscitative endovascular balloon occlusion of the aorta (REBOA) in a porcine model of hemorrhagic shock
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Hoareau, Guillaume L. (ORCID:0000000286353960)↗
SEARCH · Engineering Papers
Results for “AORTA”
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Corin is highly expressed in atherosclerosis models
Highlights: • Tested the efficacy of different commercial corin antibodies. • Corin was basally expressed in aorta and induced in atherosclerotic mouse model. • Corin was expressed in vascular endothelial cells and induced by ox-LDL stimulation. • Demonstrated corin involvement in atherosclerosis. Corin is a serine protease mainly expressed in the heart, where it regulates blood pressure and cardiac function through activating pro-atrial natriuretic peptide (pro-ANP) to ANP. Its expression has also been detected in non-cardiac tissues. However, there is no report so far about the distribution and function of corin in aorta and in related diseases such as atherosclerosis. This study was the first to explore corin expression in aorta both under normal conditions and in atherosclerosis models. In vivo, we found corin had a basal level of expression in aortas, mainly in intimal endothelial cells and was significantly elevated in mouse atherosclerosis model. Moreover, we observed pro-ANP, the specific substrate of corin, was also expressed in mice aortas and increased in mouse atherosclerosis model. In vitro, we further demonstrated corin expression in cultured vascular endothelial cells and its induced expression after ox-LDL stimulation. Our results suggested that corin may play important roles in aorta physiology and in the pathophysiological process of atherosclerosis in an autocrine manner and has potential clinical value for the treatment of atherosclerosis.
60 APPLIED LIFE SCIENCES↗
Evidence that simulated microgravity may alter the vascular nonreceptor tyrosine kinase second messenger pathway
Simulated microgravity (hind limb unweighting; HU) reduces maximal contractile capacity to norepinephrine (NE) but not 5-hydroxytryptamine (5-HT) in the rat abdominal aorta of male Wistar rats. Our earlier study showed that voltage-operated calcium channels, the MAPK pathway [1], and vasoconstrictive prostaglandins contribute to the NE-induced contraction of control (C) but not HU, aorta rings. Genistein, a general tyrosine kinase inhibitor, caused a significant reduction in vascular contractility in C but not HU arteries. The present study explored the role of protein kinase C (PKC) and extracellular receptor-activated kinase 1 and 2 (ERK1/2) in the HU-induced vascular hyporesponsiveness to NE. Microgravity was simulated in Wistar rats by 20 day HU. The abdominal aorta was removed from control and HU rats, cut into 3 mm rings, and mounted in tissue baths to measure isometric contraction. Protein levels were determined using Western blot analysis. PD98059, a selective MAPKK inhibitor, caused a marked inhibition of NE-induced contraction in both C and HU arteries. Calphostin C, a PKC inhibitor, completely abolished the contractile response to NE in both C and HU tissues. Phosphorylated (activated) ERK1/2 protein mass was greater in C, compared to HU, aortas, and was reduced by genistein only in C tissues. MAPK total protein levels in the rat aorta were increased in the HU-treated, compared to C, animals. These results indicate that PKC represents an early transduction step in the contractile response to NE in the rat abdominal aorta. That inhibition of the step immediately before activation of MAPK reduced contraction in both C and HU tissues, while general tyrosine kinase inhibition with genistein blocked only the control responses, suggests that a nonreceptor tyrosine kinase may be involved in HU-induced vascular hyporesponsiveness to NE.
Non-NASA Center↗
Endoplasmic reticulum stress involved in high-fat diet and palmitic acid-induced vascular damages and fenofibrate intervention
Fenofibrate (FF) is widely used to lower blood lipids in clinical practice, but whether its protective effect on endothelium-dependent vasodilatation (EDV) in thoracic aorta is related with endoplasmic reticulum (ER) stress remains unknown. In this study, female Sprauge Dawley rats were divided into standard chow diets (SCD), high-fat diets (HFD) and HFD plus FF treatment group (HFD + FF) randomly. The rats of latter two groups were given HFD feeding for 5 months, then HFD + FF rats were treated with FF (30 mg/kg, once daily) via gavage for another 2 months. The pathological and tensional changes, protein expression of eNOS, and ER stress related genes in thoracic aorta were measured. Then impacts of palmitic acid (PA) and FF on EDV of thoracic aorta from normal female SD rats were observed. Ultimately the expression of ER stress related genes were assessed in primary mouse aortic endothelial cells (MAEC) treated by fenofibric acid (FA) and PA. We found that FF treatment improved serum lipid levels and pathological changes in thoracic aorta, accompanied with decreased ER stress and increased phosphorylation of eNOS. FF pretreatment also improved EDV impaired by different concentrations of PA treatment. The dose- and time-dependent inhibition of cell proliferation by PA were inverted by FA pretreatment. Phosphorylation of eNOS and expression of ER stress related genes were all inverted by FA pretreatment in PA-treated MAEC. Our findings show that fenofibrate recovers damaged EDV by chronic HFD feeding and acute stimulation of PA, this effect is related with decreased ER stress and increased phosphorylation of eNOS. - Highlights: • Fenofibrate treatment improved pathological changes in thoracic aorta by chronic high-fat-diet feeding. • Fenofibrate pretreatment improved endothelium-dependent vasodilation impaired by different concentrations of palmitic acid. • The inhibition of proliferation in endothelial cells by palmitic acid were inverted by fenofibric acid. • Phosphorylation of eNOS and expression of ER stress related genes were inverted by fenofibrate or fenofibric acid.
60 APPLIED LIFE SCIENCES↗
Factors Affecting Optimal Aortic Remodeling After Thoracic Endovascular Aortic Repair of Type B (IIIb) Aortic Dissection
PurposeThe purpose of this study was to determine factors associated with entire aortic remodeling after thoracic endovascular aortic repair (TEVAR) in patients with type B dissection.Materials and MethodsThe patients with type B (IIIb) dissections who underwent TEVAR from 2006 to 2013 with minimum of 2 years of follow-up computed tomography data were retrospectively reviewed. Based on the status of false lumen remodeling of entire aorta, patients were divided into three groups: complete regression, total thrombosis, and inadequate regression with patent abdominal false lumen.ResultsA total of 90 patients (72 males, 18 females; mean age 56.6 ± 16.4 years) were included and divided into the complete regression (n = 22), total thrombosis (n = 18), and inadequate regression (n = 50) groups. Multivariate logistic regression analysis indicated that dissection extension to iliac arteries, increased preoperative number of dissection tear over abdominal aorta, and decreased preoperative abdominal aorta bifurcation true lumen ratio, as compared between the inadequate and complete regression groups, were associated with a persistent false lumen (odds ratio = 33.33, 2.304, and 0.021; all, p ≤ 0.012). Comparison of 6, 12, and 24 months postoperative data revealed no significant differences at any level, suggesting that the true lumen area ratio might not change after 6 months postoperatively.ConclusionsIncreased preoperative numbers of dissection tear around the abdominal visceral branches, dissection extension to the iliac arteries, and decreased preoperative true lumen area ratio of abdominal aorta are predictive of entire aortic remodeling after TEVAR in patients with type B dissection.Level of EvidenceIII.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Comparison of Chimney Technique and Single-Branched Stent Graft for Treating Patients with Type B Aortic Dissections that Involved the Left Subclavian Artery
Objective: To compare the short-term efficiency of two different endovascular repairs for type B aortic dissection involving the left subclavian artery. Methods: From February 2013 to March 2016, a cohort of 43 patients with TBADs involving the LSA underwent thoracic endovascular aortic repair (TEVAR) in two departments, consisting of 22 (Group A) with chimney grafts (CGs) and 21 (Group B) with single-branched stent graft (SBSG). Results of the two groups in perioperative and follow-up period (≥ 3 months) were comparatively analyzed, especially on aortic remodeling. Results: Endoluminal repair of the two groups was successfully carried out. The median follow-up period was 19 months (range, 3–43 months) in Group A and 12 months in Group B (range, 6–32 months). During the TEVAR, one CG compression occurred in Group A and one type I endoleak in Group B. During follow-up, four complications occurred in Group A (two CGs occlusion, one type I endoleak and one death from dissecting aneurysm rupture), compared with two occurred in Group B (one sidearm graft twist and one death from myocardial infarction). Complete thrombosis of the false lumen (FL) in thoracic aorta was revealed in 83.3% (15/18) cases in Group A and 89.5% (17/19) in Group B. Partial thrombosis of the FL was revealed in 16.7% (3/18) cases in Group A and 10.5% (2/19) in Group B. In the abdominal aorta, complete thrombosis of the FL was noted in 23.1% (3/13) cases in Group A and 36.4% (4/11) in Group B. Partial thrombosis of the FL was revealed in 76.9% (10/13) cases in Group A and 63.6% (7/11) in Group B. Significant true lumen re-expansion and false lumen regression were observed in different levels of the descending aorta by computed tomography angiography (CTA) in both Groups A and B (P < 0.05). No significant diametric changes of abdominal aorta were found during follow-up in both groups. Conclusions: For patients with TBADs involving the LSA, the chimney technique and the SBSG revealed comparable results. Further evaluation of more patients with longer follow-up is needed to substantiate these results.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Silenced long non-coding RNA activated by DNA damage elevates microRNA-495-3p to suppress atherosclerotic plaque formation via reducing Krüppel-like factor 5
Objective: Atherosclerosis (AS) is an inflammatory disease and the formation of atherosclerotic plaque plays a critical role in AS progression. We aimed to investigate the effect of long non-coding RNA (lncRNA) activated by DNA damage (NORAD)/microRNA-495-3p (miR-495-3p)/Krüppel-like factor 5 (KLF5) axis on atherosclerotic plaque formation. Methods: The ApoE{sup −/-} mice were fed a high-fat diet to construct AS mouse models and the modeled mice were treated with altered NORAD, miR-495-3p or KLF5. NORAD, miR-495-3p and KLF5 expression in mouse aorta tissues were evaluated, and the levels of inflammatory factors, oxidative stress factors, endothelial function indices and blood lipid in mice were all determined. The atherosclerotic plaque area, lipid deposition area, collagen fibers and CD68 expression in mouse aorta tissues were assessed. The regulatory relation between NORAD and miR-495-3p, and the target relation between miR-495-3p and KLF5 were confirmed. Results: NORAD and KLF5 were increased whereas miR-495-3p was decreased in atherosclerotic mouse aortas. Inhibited NORAD or elevated miR-495-3p suppressed inflammation, oxidative stress, endothelial dysfunction, blood lipid level, atherosclerotic plaque area, collagen fibers and CD68 expression in atherosclerotic mouse aortas. Effects of elevated miR-495-3p on atherosclerotic mice could be reversed by up-regulation of KLF5. NORAD served as a sponge of miR-495-3p and miR-495-3p directly targeted KLF5. Conclusion: Silenced NORAD elevated miR-495-3p to suppress atherosclerotic plaque formation via reducing KLF5. Findings in our research may be helpful for exploring molecular mechanisms of AS.
60 APPLIED LIFE SCIENCES↗
Cardiovascular Responses to Simulated Spaceflight: Molecular Signatures and Surrogate Outputs to Measure CVD Risk
During extended space missions beyond low Earth orbit, astronauts will encounter prolonged periods of weightlessness and low dose space radiation. Previous studies have shown that exposure to small doses of high LET radiation (< 50 cGy) can lead to both short-term and long-term alterations in heart function, structure and underlying molecular mechanisms. In this study, we aim to identify the molecular signature associated with the cardiovascular response to simulated galactic cosmic radiation (5-ion GCR) alone or in combination with simulated weightlessness at time intervals relevant to mission length and recovery. Additionally, we aim to determine whether sex impacts cardiovascular responses to these spaceflight factors. Our overarching goal is to enhance our understanding of the cardiovascular risks associated with extended space missions and the clinical endpoints they suggest. We hypothesize that exposure to simulated space radiation leads to enduring alterations in the transcriptome, redox signaling and cytokine environment of cardiovascular tissue, some which have known links with reduced cardiovascular performance, aging, and increased risk of cardiovascular disease (CVD). Furthermore, we posit that simulated space radiation exposure in combination with simulated microgravity exacerbates cardiovascular deficits compared to single factor exposure. Female and male C57BL/6J mice, aged 23-24 weeks, were exposed to a single dose of 5, 15, or 50 cGy of 5-ion GCR, or sham-treated (0 cGy). Euthanasia was performed at 14 days and ~4 months post-irradiation. Hearts, aorta and blood plasma were collected shortly thereafter. RNA-sequencing of left ventricles at ~4 months post-GCR exposure revealed sex differences in the heart transcriptome with a few genes showing radiation-dependent changes in expression levels. Notably, some of the differentially expressed genes in 15 and 50 cGy GCR groups are known to play roles in the development of CVD. Analysis of protein levels of a subset of inflammatory cytokines in the heart indicated sex differences but no differences between sham and 50 cGy groups. Results also showed correlations among differentially expressed genes and a subset of inflammatory cytokines, with some correlations altered by GCR exposure. These findings suggest that GCR exposure can modify protein and gene networks linked to inflammation and CVD progression. In the aorta, telomere lengths were comparable across treatment groups sexes. Mitochondrial copy number is a biomarker for mitochondrial function with decreased copy numbers associated with cardiometabolic disease traits. Mitochondrial copy numbers of aorta also showed no sex nor dose differences. In a second study, mice underwent one week of simulated microgravity by hindlimb unloading (HU) and then exposed to a single dose of 15 cGy of 5-ion GCR. HU was conducted for an additional two weeks following GCR exposure. Single factor exposure groups (HU or GCR only) also were included in the study. Euthanasia was then performed and the same tissues were collected. Protein levels of select inflammatory cytokines in the heart showed sex-dependent differences in expression. In the aorta, telomere lengths and mitochondrial copy number also showed sex differences. In summary, our results indicate differences between sexes in biomarkers related to cardiovascular health. Exposure to 5-ion GCR or HU, alone or in combination, did not result in changes in most of the cardiovascular biomarkers that were examined. However, in the heart, simulated space radiation at doses of 15 and 50 cGy led to long-term alterations in the expression levels of a small group of genes known to be associated with the progression of CVD. The long-term transcriptomic changes resulting from exposure to simulated space radiation should be carefully investigated to mitigate adverse cardiovascular events during and after deep space missions. Our results also highlight the importance of sex-specific strategies in monitoring and maintaining cardiovascular health during and after deep space missions.
cardiovascular↗
Design, synthesis, and antihypertensive activity of new pyrimidine derivatives endowing new pharmacophores
A new series of achiral pyrimidine derivatives based on nifedipine-like structure was designed and synthesized. These pyrimidyl derivatives contained hydrazine, hydrazones, acetohydrazide, differently substituted benzylidene functionalities, benzosulfohydrazine, various heterocycles such as pyrazole, pyrazolidinedione, thiazoline, and thiazolidinone rings, and fused ring systems such as triazolopyrimidine and pyrimidotriazine rings. Compounds 5a, 5b, 11b, 8b, 9b–d, and 15b showed a decrease in mean arterial rabbit blood pressure (MABP) ranging from 51.4 to 78.2 mmHg in rabbits in comparison with nifedipine-treated rabbits. Among these derivatives, compounds 5a, 5b, 9b, and 9c were found to exhibit calcium channel blockade activity on preparations of rabbit aortae. They exhibited relaxation in the range of 89.2% to 74.4% in comparison to nifedipine (57.6%) as well as a decrease in heart rate. Histopathological effect of compounds 5a,b on the expression of endothelial nitric oxide synthase (eNOS) was also examined on rat aorta. An intense expression of eNOS immune staining in aortic endothelium was seen for compound 5b indicating that it lowered blood pressure via activation of eNOS expression in aorta.
60 APPLIED LIFE SCIENCES↗
Liver metastases of neuroendocrine tumors: is it possible to diagnose different histologic subtypes depending on multiphasic CT features?
Purpose: To assess and compare the multiphasic computed tomography (CT) features of neuroendocrine tumor (NET) liver metastases and to investigate the possibility to predict the histologic subtype of the primary tumor. Materials and methods: Between January 2013 and December 2017 patients with biopsy proven NET with at least one liver metastasis who underwent multiphasic CT were enrolled in this study. All cases were acquired using a standardized multiphasic liver CT protocol, arterial, portal, and hepatic venous phases were obtained. Images were retrospectively analyzed in consensus by two abdominal radiologists blinded to clinical data and histologic subtype. The size, number, and location of lesions were noted. Enhancement patterns of each lesion on arterial, portal, and hepatic venous phases were assessed. For quantitative analysis, CT attenuation of tumors, liver parenchyma, and aorta were measured using a circular region of interest (ROI) on arterial, portal, and hepatic venous phases for reflecting the blood supply of the tumor. Tumor-to-aorta and tumor-to-liver ratio were calculated in all three phases. Differences between subtypes of NET liver metastases were studied using ROC analysis of clustered data. Results: A total of 255 neuroendocrine tumor liver metastases divided into 101 (39.6%) pancreatic, 60 (23.5%) gastroenteric and 94 (36.8%) lung NET liver metastases were analyzed. Contrast enhancement of lesions was homogeneous in 78% of patients (n = 199), which was significantly more frequent in patients with pancreatic group than in those with gastroenteric origin (n = 90, 89.1% vs. n = 28, 46.7%; p < 0.001). Gastroenteric NET metastases frequently showed heterogeneous enhancement, which was significantly higher than in the other two groups (50% vs. 3% and 2%). With respect to the location of the primary tumor, the difference in enhancement patterns of the liver lesions was statistically significant (p < 0.001). Pancreatic NET metastases were mostly hyperdense on arterial images and isodense on portal and hepatic venous phase images (79.2%, n = 80). Gastroenteric NET metastases were mostly hyperdense on arterial phase images and hypodense on portal and hepatic venous phase images (n = 28, 46.7%). The most frequent pattern for lung NET metastases was hypoattenuation on all three phase images (n = 44, 46.8%). ROC analysis of clustered data revealed statistically significant differences between pancreatic NET liver metastases, gastroenteric NET liver metastases, and lung NET liver metastases in terms of tumor-to-aorta (T–A) ratio and tumor-to-liver (T–L) ratio (p < 0.001). Conclusion: We observed statistically significant differences in multiphasic CT features (enhancement pattern, T–A ratio, and T–L ratio) between histologic subtypes of NET liver metastases. As the difference in histological subtypes of NET liver metastases results in a different prognosis and different management strategy, these CT features might help to identify the primary tumor when it is not known to ensure accurate tumor staging and to provide optimal treatment.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Early Results of Chimney Technique for Type B Aortic Dissections Extending to the Aortic Arch
ObjectiveTo summarize our early experience gained from the chimney technique for type B aortic dissection (TBAD) extending to the aortic arch and to evaluate the aortic remodeling in the follow-up period.MethodsFrom September 2011 to July 2014, 27 consecutive TBAD patients without adequate proximal landing zones were retrograde analyzed. Chimney stent-grafts were deployed parallel to the main endografts to reserve flow to branch vessels while extending the landing zones. In the follow-up period, aortic remodeling was observed with computed tomography angiography.ResultsThe technical success rate was 100 %, and endografts were deployed in zone 0 (n = 3, 11.1 %), zone 1 (n = 18, 66.7 %), and zone 2 (n = 6, 22.2 %). Immediately, proximal endoleaks were detected in 5 patients (18.5 %). During a mean follow-up period of 17.6 months, computed tomography angiography showed all the aortic stent-grafts and chimney grafts to be patent. Favorable remodeling was observed at the level of maximum descending aorta and left subclavian artery with expansion of true lumen (from 18.4 ± 4.8 to 25 ± 0.86 mm, p < 0.001 and 27.1 ± 0.62 to 28.5 ± 0.37 mm, p < 0.001) and depressurization of false lumen (from 23.7 ± 2.7 to 8.7 ± 3.8 mm, p < 0.001, from 5.3 ± 1.2 to 2.1 ± 2.1 mm, p < 0.001). While at the level of maximum abdominal aorta, suboptimal remodeling of the total aorta (from 24.1 ± 0.4 to 23.6 ± 1.5 mm, p = 0.06) and true lumen (from 13.8 ± 0.6 to 14.5 ± 0.4 mm, p = 0.08) was observed.ConclusionBased on our limited experience, the chimney technique with thoracic endovascular repair is demonstrated to be promising for TBAD extending to the arch with favorable aortic remodeling.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Endovascular Neck Stabilization Before EVAR for Infrarenal Aortic Aneurysm in Chronic Aortic Dissection
Background: Endovascular treatment of infrarenal abdominal aortic aneurysm (AAA) with proximal chronic aortic dissection is challenging as a false and true lumen at the level of the infra-renal neck does not allow a sufficient landing zone. We describe staged endovascular neck stabilization prior to standard endovascular aortic repair (EVAR) for AAA with chronic aortic dissection. Technique: To create a stable proximal neck (PN) by closing entry tears, thereby resulting in total false lumen thrombosis (FLT) prior to standard EVAR. Case 1 false lumen fenestrations were present at the descending aorta, the right renal artery orifice and PN. After closing the entry tear by thoracic EVAR, an aortic cuff was placed in the true lumen of the PN and renal stenting for the right renal artery was performed. After 2 months, total FLT was achieved, and EVAR was performed. Case 2 false lumen fenestrations were present at the descending, super celiac aorta and PN. After closing the entry by TEVAR, aortic cuffs were placed at infrarenal aorta to close residual entries. After 1 month of achieving total FLT, EVAR was performed. Both cases had no type 1 endoleak during follow-up. Conclusion: The endovascular neck stabilization is a useful treatment option that facilitates standard EVAR for AAA in chronic aortic dissection.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Is coronary calcium scoring too late? Total body arterial calcium burden in patients without known CAD and normal MPI
Background: Patients with normal myocardial perfusion imaging (MPI) have a good prognosis. However, pre-clinical coronary and extracoronary atherosclerosis may exist in the absence of myocardial ischemia. Methods: 154 Egyptian patients (mean age 53 years) underwent whole-body non-contrast CT following normal MPI. Results: Atherosclerosis in the form of calcification was observed in ≥1 vascular bed in 115 of 154 (75%) patients. This included the iliofemoral (62%), abdominal aorta (53%), thoracic aorta (47%), coronary (47%), and carotid (25%) vascular beds. Mean total body calcium score was 3172 ± 530 AU. Extracoronary atherosclerosis in patients with a zero coronary artery calcium (CAC) score was common, occurring in the above-listed beds 42%, 36%, 29%, and 7% of the time, respectively. CAC was rarely present without iliofemoral or abdominal aortic calcification. Conclusion: Quantitative assessment of calcification in different vascular beds demonstrates that extracoronary atherosclerosis is common in patients who have normal MPI. Atherosclerotic calcifications are most common in the iliofemoral arteries and abdominal aorta, which typically predate coronary calcifications. An imaging strategy to detect extracoronary atherosclerosis could lead to greater understanding of the natural history of atherosclerosis in its long pre-clinical phase and possibly to earlier preventive strategies.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Endothelin-1 exacerbates development of hypertension and atherosclerosis in modest insulin resistant syndrome
Endothelin-1 (ET-1) is known as potent vasoconstrictor, by virtue of its mitogenic effects, and may deteriorate the process of hypertension and atherosclerosis by aggravating hyperplasia and migration in VSMCs. Our previous study demonstrated that insulin infusion caused sequential induction of hyperinsulinemia, hyperendothelinemia, insulin resistance, and then hypertension in rats. However, the underlying mechanism of ET-1 interfere insulin signaling in VSMCs remains unclear. To characterize insulin signaling during modest insulin resistant syndrome, we established and monitored rats by feeding high fructose-diet (HFD) until high blood pressure and modest insulin resistance occurred. To explore the role of ET-1/ET{sub A}R during insulin resistance, ET{sub A}R expression, ET-1 binding, and insulin signaling were investigated in the HFD-fed rats and cultured A-10 VSMCs. Results showed that high blood pressure, tunica medial wall thickening, plasma ET-1 and insulin, and accompanied with modest insulin resistance without overweight and hyperglycemia occurred in early-stage HFD-fed rats. In the endothelium-denuded aorta from HFD-fed rats, ET{sub A}R expression, but not ET{sub B}R, and ET-1 binding in aorta were increased. Moreover, decreasing of insulin-induced Akt phosphorylation and increasing of insulin-induced ERK phosphorylation were observed in aorta during modest insulin resistance. Interestingly, in ET-1 pretreated VSMCs, the increment of insulin-induced Akt phosphorylation was decreased whereas the increment of insulin-induced ERK phosphorylation was increased. In addition, insulin potentiated ET-1-induced VSMCs migration and proliferation due to increasing ET-1 binding. ETAR antagonist reversed effects of ET-1 on insulin-induced signaling and VSMCs migration and proliferation. In summary, modest insulin resistance syndrome accompanied with hyperinsulinemia leading to the potentiation on ET-1-induced actions in aortic VSMCs. ET-1 via ET{sub A}R pathway suppressed insulin-induced AKT activation, whereas remained insulin-induced ERK activation. ET-1 and insulin synergistically potentiated migration and proliferation mainly through ET{sub A}R/ERK dependent pathway, which is dominant in VSMCs during modest insulin resistance syndrome. Therefore, ET-1 and ET{sub A}R are potential targets responsible for the observed synergism effect in the hypertensive atherosclerotic process through enhancement of ET-1 binding, ET-1 binding, ET{sub A}R expression, and ET-1-induced mitogenic actions in aortic VSMCs. - Highlights: • ET-1/ET{sub A}R signaling and insulin-induced pERK were high in modest insulin resistance. • ET-1 via ET{sub A}R suppressed insulin-induced pAKT but remained intact pERK in VSMCs. • Insulin potentiated ET-1-induced VSMC mitogenic action was ET{sub A}R/ERK dependent.
60 APPLIED LIFE SCIENCES↗
Endothelial ATP-binding cassette G1 in mouse endothelium protects against hemodynamic-induced atherosclerosis
Activated vascular endothelium inflammation under persistent hyperlipidemia is the initial step of atherogenesis. ATP-binding cassette G1 (ABCG1) is a crucial factor maintaining sterol and lipid homeostasis by transporting cholesterol efflux to high-density lipoprotein. In this study, we investigated the protective effects of ABCG1 in endothelial inflammation activation during early-stage atherogenesis in mice and the underlying mechanisms. Endothelial cell (EC)-specific ABCG1 transgenic (EC-ABCG1-Tg) mice were generated and cross-bred with low-density lipoprotein receptor–deficient (Ldlr{sup −/−}) mice. After a 4-week Western-type diet, the mice were sacrificed for assessing atherosclerosis. Human umbilical vein ECs were treated with different flows, and ABCG1 was adenovirally overexpressed to investigate the mechanism in vitro. Compared with Ldlr{sup −/−} mouse aortas, EC-ABCG1-Tg/Ldlr{sup −/−} aortas showed decreased early-stage lesions. Furthermore, the lesion area in the EC-ABCG1-Tg/Ldlr{sup −/−} mouse aortic arch but not thoracic aorta was significantly reduced, which suggests a protective role of ABCG1 under atheroprone flow. In vitro, overexpression of ABCG1 attenuated EC activation caused by oscillatory shear stress. Overexpression of ABCG1 blunted cholesterol-activated ECs in vitro. In exploring the mechanisms of ABCG1 attenuating endothelial inflammation, we found that ABCG1 inhibited oscillatory flow-activated nuclear factor kappa B and NLRP3 inflammasome in ECs. ABCG1 may play a protective role in early-stage atherosclerosis by reducing endothelial activation induced by oscillatory shear stress via suppressing the inflammatory response. - Highlights: • EC-ABCG1-Tg mice in a Ldlr{sup −/−} background showed decreased atherosclerosis. • Overexpression of ABCG1 in ECs decreased OSS-induced EC activation. • NLRP3 and NF-κB might be an underlying mechanism of ABCG1 protective role.
60 APPLIED LIFE SCIENCES↗
Transplantation of periaortic adipose tissue inhibits atherosclerosis in apoE −/− mice by evoking TGF-β1-mediated anti-inflammatory response in transplanted graft
Highlights: • Transplantation of tPAT reduces the plaque size in apoE{sup -/-} mice, concomitant with increased serum TGF-β1levels. • TGF-β1 levels show significant inverse correlation with plaque size in tPAT-transplanted mice. • Neutralizing TGF-β antibody abrogates anti-atherogenic effect of tPAT transplantation. • TGF-β-positive staining is colocalized with Mac-2-positive cells in grafted tPAT. • mRNA expression levels of alternatively activated macrophages genes and IL-4 are significantly increased in grafted tPAT. Perivascular adipose tissue (PAT) is associated with vascular homeostasis; however, its causal effect on atherosclerosis currently remains undefined. Here, we investigated the effect of experimental PAT transplantation on atherosclerosis. The thoracic periaortic adipose tissue (tPAT) was dissected from 16-week-old wild-type mice and transplanted over the infrarenal aorta of 20-week-old apoE deficient (apoE{sup −/−}) mice fed high-cholesterol diet for 3 months. Oil-red O staining after 4 weeks showed a significant 20% decrease in the atherosclerotic lesion of suprarenal aorta compared with that of sham control mice, while that of infrarenal aorta showed no difference between the two groups. TGF-β1 mRNA expression was significantly higher in grafted tPAT than donor tPAT, accompanied by a significant increase in serum TGF-β1 concentration, which was inversely correlated with the suprarenal lesion area (r = −0.63, P = 0.012). Treatment with neutralizing TGF-β antibody abrogated the anti-atherogenic effect of tPAT transplantation. Immunofluorescent analysis of grafted tPAT showed that TGF-β-positive cells were co-localized with Mac-2-positive cells and this number was significantly increased compared with donor tPAT. There was also marked increase in mRNA expression of alternatively activated macrophages-related genes. Furthermore, the percentage of eosinophils in stromal vascular fraction of donor tPAT was much higher than that in epididymal white adipose tissue, concomitant with the significantly higher protein level of IL-4. IL-4 mRNA expression levels in grafted tPAT were increased in a time-dependent manner after tPAT transplantation. Our findings show that tPAT transplantation inhibits atherosclerosis development by exerting TGF-β1-mediated anti-inflammatory response, which may involve alternatively activated macrophages.
60 APPLIED LIFE SCIENCES↗
Enhanced calcium entry via activation of NOX/PKC underlies increased vasoconstriction induced by methylglyoxal
Advanced glycation end-products (AGEs) play a pivotal role in macro- and micro-vascular diabetic complications. We investigated the mechanism by which methylglyoxal (an endogenous generator of AGEs) affects vascular contractility using the isolated artery technique. Contractile responses to vasoconstrictors phenylephrine (PE), angiotensin II (Ang II), vasopressin (VP) and KCl were measured in the isolated rat aorta following one-our exposure to methylglyoxal (50–200 μM). The perfused rat kidney was employed to confirm the effect of methylglyoxal on microvessels. Methylglyoxal-induced changes in cytosolic calcium were measured in the smooth muscle layer of the aorta with the calcium-sensing fluorophore Fluo-4 AM. Methylglyoxal significantly increased maximal contraction of the rat aorta to PE, Ang II and VP. Similar results were seen in response to the depolarizing vasoconstrictor KCl in macro and micro vessels. The methylglyoxal-induced increases in aortic contraction mediated by the agonist and KCl were endothelium independent. Methylglyoxal-induced increases in KCl-dependent aortic contraction were abolished after the removal of extracellular calcium or in the presence of the calcium channel blocker nifedipine. Incubation with the antioxidant N-acetyl-l-cysteine (NAC), apocynin (a nonselective NADPH oxidase (NOX) inhibitor) or chelerythrine (a protein kinase C (PKC) inhibitor) prior to methylglyoxal pre-treatment reversed the methylglyoxal-induced increases in the rat aortic contractility. In conclusion, the formation of AGEs increases vasoconstriction of both macro- and micro-vessels by increasing the voltage-activated calcium entry in vascular smooth muscles in a NOX and PKC dependent manner.
60 APPLIED LIFE SCIENCES↗
Mercury-induced vascular dysfunction is mediated by angiotensin II AT-1 receptor upregulation
Highlights: • Chronic exposure to Hg promotes Ang II AT-1 receptors upregulation in aorta. • Ang II AT-1 receptors activation induces vascular damage in rats exposed to Hg. • Upregulation of Ang II AT-1 receptors by Hg increases ROS and prostanoids levels. • Oxidative stress caused by Ang II AT-1 receptors activation reduces NO bioavailability. Low doses of mercury (Hg) promote deleterious effects on cardiovascular system, but the mechanisms implicated remain unclear. This study analyzed whether angiotensin II AT-1 receptors are involved in the vascular dysfunction caused by chronic exposure to low HgCl{sub 2} doses. For this, rats were divided into four groups and untreated (saline by im injections and tap water by gavage) or treated for 30 days as follows: Mercury (HgCl{sub 2} im, first dose of 4.6 µg kg{sup −1} and subsequent doses of 0.07 µg kg{sup −1} day{sup −1}, and tap water by gavage); Losartan (saline im and losartan, 15 mg kg{sup −1} day{sup −1}, by gavage); Losartan-Mercury (HgCl{sub 2} im and Losartan by gavage). Systolic blood pressure was measured by tail plethysmography, vascular reactivity in aorta by isolated organ bath, oxidative stress by measuring the levels of reactive oxygen species (ROS), malondialdehyde (MDA) and antioxidant capacity (FRAP) and protein expression of AT-1 receptors by Western Blot. As results, co-treatment with losartan prevented the increased aortic vasoconstrictor responses to phenylephrine (Phe), the involvement of ROS and prostanoids on the response to Phe and the reduced negative endothelial modulation by nitric oxide on these responses. Moreover, this co-treatment avoided the increase in plasmatic and vascular oxidative stress and AT-1 protein expression in aorta. In conclusion, these results suggest that AT-1 receptors upregulation might play a key role in the vascular damage induced by Hg exposure by increasing oxidative stress and probably by reducing NO bioavailability.
54 ENVIRONMENTAL SCIENCES↗