Aortic Intima Research Articles

Radiation Impacts Early Atherosclerosis by Suppressing Intimal LDL Accumulation

Rationale: Bone marrow transplantation (BMT) is used frequently to study the role of hematopoietic cells in atherosclerosis, but aortic arch lesions are smaller in mice after BMT. Objective: To identify the earliest stage of atherosclerosis inhibited by BMT and elucidate potential mechanisms. Methods and Results: Ldlr-/- mice underwent total body γ-irradiation, bone marrow reconstitution and 6-week recovery. Atherosclerosis was studied in the ascending aortic arch and compared to mice without BMT. In BMT mice neutral lipid and myeloid cell topography were lower in lesions after feeding a cholesterol-rich diet (CRD) for 3, 6 and 12 weeks. Lesion coalescence and height were suppressed dramatically in mice post-BMT, whereas lateral growth was inhibited minimally. Targeted radiation to the upper thorax alone reproduced the BMT phenotype. Classical monocyte recruitment, intimal myeloid cell proliferation and apoptosis did not account for the post-BMT phenotype. Neutral lipid accumulation was reduced in 5-day lesions, thus we developed quantitative assays for LDL accumulation and paracellular leakage using DiI-labeled human LDL and rhodamine B-labeled 70kD dextran. LDL accumulation was dramatically higher in the intima of Ldlr-/- relative to Ldlr+/+ mice, and was inhibited by injection of HDL mimics, suggesting a regulated process. LDL, but not dextran, accumulation was lower in mice post-BMT both at baseline and in 5-day lesions. Since the transcript abundance of molecules implicated in LDL transcytosis was not significantly different in the post-BMT intima, transcriptomics from whole aortic arch intima, and at single cell resolution, was performed to give insights into pathways modulated by BMT. Conclusions: Radiation exposure inhibits LDL entry into the aortic intima at baseline and the earliest stages of atherosclerosis. Single cell transcriptomic analysis suggests that LDL uptake by endothelial cells is diverted to lysosomal degradation and reverse cholesterol transport pathways. This reduces intimal accumulation of lipid and impacts lesion initiation and growth.

Establishment and effect evaluation of an aortic dissection model induced by different doses of β-aminopropionitrile in rats.

Given the controversy regarding the appropriate dose of β-aminopropionitrile for induction of aortic dissection models in rats, the purpose of this study was to explore the most suitable concentration of β-aminopropionitrile to establish a high-incidence and low-mortality aortic dissection model. Eighty three-week-old male Sprague-Dawley rats were equally divided into four groups: a control group, a 0.06% β-aminopropionitrile group, a 0.08% β-aminopropionitrile group and a 0.1% β-aminopropionitrile group. Initial experiments were performed on the control group, which was not treated with β-aminopropionitrile (and drank water freely), and the other three groups, which were given different concentrations of β-aminopropionitrile solution daily (0.06%, 0.08% and 0.1%). Subsequently, on the 40th day, osmotic minipumps administering 1 μg/kg per min angiotensin II (Ang II) were implanted subcutaneously into the β-aminopropionitrile groups, while the control group was continuously pumped with normal saline. The rats were euthanized 48 h after implantation. All rats that died before the expected end time of the experiment were autopsied immediately, and the aortas were dissected. The rats surviving at the end of the experiment were sacrificed by an overdose of sodium pentobarbital, and tissue samples were harvested for further analyses. The mean survival days were significantly different among the groups, with 39.1 ± 6.04 days in the 0.08% β-aminopropionitrile group and 32.7 ± 9.85 days in the 0.1% β-aminopropionitrile group (P = 0.0178) at the end of the experiment. Compared with those in the 0.06% β-aminopropionitrile group, the rates of aortic dissection were significantly higher in the 0.08% β-aminopropionitrile group and the 0.1% β-aminopropionitrile group (P = 0.0015 and P = 0.0005, respectively), while there was no significant difference between the 0.08% β-aminopropionitrile group and the 0.1% β-aminopropionitrile group (P = 0.723) at 70% and 75%, respectively. However, the rupture rates were significantly different between the 0.08% β-aminopropionitrile group and the 0.1% β-aminopropionitrile group (55% versus 20%, P = 0.022). Hematoxylin-eosin staining of the aortic tissue sections of the β-aminopropionitrile group showed that red blood cells entered the pseudocavity in the vascular wall, while the vascular wall structure of the control group was intact. Compared with control rats, which were intact and free from fracture, β-aminopropionitrile-treated rats had fewer collagen fibers and exhibited fracture. Magnetic resonance imaging showed that the aortic intimae of the aortic dissection rats showed double lumens and intimal tears. An aortic dissection model with a high incidence and low mortality was successfully and stably developed with 0.08% β-aminopropionitrile. This model will enable further studies investigating aortic dissection pathogenesis and drug therapy. Magnetic resonance imaging may be a reliable technique for imaging the aorta in rats.

Inhibition of miR-122 reduced atherosclerotic lesion formation by regulating NPAS3-mediated endothelial to mesenchymal transition

AimsEndothelial to mesenchymal transition (EndMT) is closely related to atherosclerosis. Herein, we aim to determine whether miR-122 is involved in EndMT and the underlying mechanism in atherosclerosis. Main methodsqRT-PCR was performed to detect miR-122 expression in ApoE−/− mice and cellular EndMT model induced by H2O2. MiR-122 expression in vivo was modulated by lenti-virus injection and by genetic manipulation. Hematoxylin and eosin (HE) and Oil-red O staining were used to observe the plaque size and lipid accumulation in the aortic roots. F4/80 staining, elastin staining, and masson staining were used to observe the components of atherosclerotic lesions. MiR-122 expression in endothelial cells was modulated by transfection of miR-122 mimic and inhibitor. Western blotting and co-localization of endothelial markers (VE-cadherin, CD31) and mesenchymal markers (Vimentin, α-SMA) were carried out to determine EndMT. Key findingsMiR-122 was upregulated in the aortic intima and serum of ApoE−/− mice induced by HFD and in cellular EndMT model. Inhibition of miR-122 repressed the atherosclerotic plaque progression and vulnerable plaque formation in ApoE−/− mice. In vitro, endothelial cells acquired a spindle-shaped morphology accompanying decrease of the endothelial markers (VE-cadherin, CD31) and increase of the mesenchymal markers (Vimentin, α-SMA) in the presence of H2O2, which was inhibited by miR-122 inhibitor. Furthermore, NPAS3 functions as a target of miR-122, and NPAS3 silencing abolished the anti-EndMT effect of miR-122 inhibitor. SignificanceInhibition of miR-122 prevents atherosclerosis and regulates NPAS3-mediated EndMT, suggesting that miR-122 may be a novel target in the treatment of EndMT-associated diseases including atherosclerosis.

Adiponectin in normal and atherosclerotic intima of human aorta: Analysis of its localization and sources

Background and Aims: Earlier we have shown that adipose tissue hormone adiponectin is accumulated in stable and unstable atherosclerotic plaques of human aorta. The current study is undertaken to find out, first, if adiponectin is also localized in normal aortic intima, and, second, if adiponectin is synthesized locally in normal aortic intima or plaques, or it goes there from plasma.

A macrophage-specific lncRNA regulates apoptosis and atherosclerosis by tethering HuR in the nucleus

Long non-coding RNAs (lncRNAs) are emerging regulators of pathophysiological processes including atherosclerosis. Using RNA-seq profiling of the intima of lesions, here we identify a macrophage-specific lncRNA MAARS (Macrophage-Associated Atherosclerosis lncRNA Sequence). Aortic intima expression of MAARS increases by 270-fold with atherosclerotic progression and decreases with regression by 60%. MAARS knockdown reduces atherosclerotic lesion formation by 52% in LDLR−/− mice, largely independent of effects on lipid profile and inflammation, but rather by decreasing macrophage apoptosis and increasing efferocytosis in the vessel wall. MAARS interacts with HuR/ELAVL1, an RNA-binding protein and important regulator of apoptosis. Overexpression and knockdown studies verified MAARS as a critical regulator of macrophage apoptosis and efferocytosis in vitro, in an HuR-dependent manner. Mechanistically, MAARS knockdown alters HuR cytosolic shuttling, regulating HuR targets such as p53, p27, Caspase-9, and BCL2. These findings establish a mechanism by which a macrophage-specific lncRNA interacting with HuR regulates apoptosis, with implications for a broad range of vascular disease states.

Endogenous neuraminidase expression in atherosclerotic lesions of human aortic intima

Background and Aims: Desialylation is a certain type of low density lipoprotein (LDL) atherogenic modification; it may occur in arterial wall due to the action of endogenous neuraminidases (NEUs). This study was undertaken to test the above hypothesis.

Abstract 13202: LncRNA-MAP3K4 Regulates Vascular Inflammation Through a P38 MAPK Signaling Pathway and Cis -modulation of MAP3K4

Introduction: Long non-coding RNAs (lncRNAs) are emerging regulators of biological processes in the vessel wall; however, their role in vascular inflammation remains poorly understood. Hypothesis: Identification of inflammation-responsive lncRNAs expressed in the aortic intima may provide novel mechanistic insights in vascular inflammation. Methods: Using RNA-Seq profiling to identify a lncRNA derived specifically from the aortic intima of atherosclerotic mice, we discovered an inflammation-responsive lncRNA, lncRNA-MAP3K4, and evaluated its role in the mechanisms mediating vascular cell inflammation. Results: Aortic expression of lncRNA-MAP3K4 , an intima-enriched and polyadenylated lncRNA , was reduced by 50% with atherosclerotic progression and by 75% following LPS-induced endotoxemia in mice. GapmeR-mediated silencing of lncRNA-MAP3K4 potently reduced mRNA and protein expression of adhesion molecules or chemokines (e.g. ICAM-1, E-selectin, MCP-1) in endothelial cells via a p38-MAPK pathway, and decreased PBMC adhesion to endothelium by 40%. Moreover, lncRNA-MAP3K4 knockdown also reduced inflammatory markers in vascular smooth muscle cells and macrophages. Analyzing the lncRNA-MAP3K4 locus, we found MAP3K4, an upstream kinase of the MAPK cascade, shared the promoter region with lncRNA-MAP3K4. In vitro and in vivo, lncRNA-MAP3K4 and MAP3K4 showed parallel inflammation-responsive expression patterns. lncRNA-MAP3K4 knockdown reduced mRNA and protein expression of MAP3K4 in cis in vessel wall cell types. ChIP-seq data showed chromatin modifications and bidirectional promoter characteristics in the lncRNA-MAP3K4/ MAP3K4 promoter region. MAP3K4 knockdown showed a similar anti-inflammation phenotype as lncRNA-MAP3K4 via a p38-MAPK pathway and cooperativity with lncRNA-MAP3K4 . Conclusions: Deficiency of lncRNA-MAP3K4 markedly reduced inflammation in vascular cells via a p38-MAPK pathway and cis -regulation of MAP3K4 from a shared bidirectional promoter. This study illustrated a divergently transcribed lncRNA/protein-coding gene pair involved in vascular inflammation and more broadly informs a better understanding of mammalian genome regulatory mechanisms in vascular disease states.

LncRNA-MAP3K4 regulates vascular inflammation through the p38 MAPK signaling pathway and cis-modulation of MAP3K4.

Chronic vascular inflammation plays a key role in the pathogenesis of atherosclerosis. Long non-coding RNAs (lncRNAs) have emerged as essential inflammation regulators. We identify a novel lncRNA termed lncRNA-MAP3K4 that is enriched in the vessel wall and regulates vascular inflammation. In the aortic intima, lncRNA-MAP3K4 expression was reduced by 50% during the progression of atherosclerosis (chronic inflammation) and 70% during endotoxemia (acute inflammation). lncRNA-MAP3K4 knockdown reduced the expression of key inflammatory factors (eg, ICAM-1, E-selectin, MCP-1) in endothelial cells or vascular smooth muscle cells and decreased monocytes adhesion to endothelium, as well as reducing TNF-α, IL-1β, COX2 expression in macrophages. Mechanistically, lncRNA-MAP3K4 regulates inflammation through the p38 MAPK signaling pathway. lncRNA-MAP3K4 shares a bidirectional promoter with MAP3K4, an upstream regulator of the MAPK signaling pathway, and regulates its transcription in cis. lncRNA-MAP3K4 and MAP3K4 show coordinated expression in response to inflammation in vivo and in vitro. Similar to lncRNA-MAP3K4, MAP3K4 knockdown reduced the expression of inflammatory factors in several different vascular cells. Furthermore, lncRNA-MAP3K4 and MAP3K4 knockdown showed cooperativity in reducing inflammation in endothelial cells. Collectively, these findings unveil the role of a novel lncRNA in vascular inflammation by cis-regulating MAP3K4 via a p38 MAPK pathway.

LncRNA VINAS regulates atherosclerosis by modulating NF-κB and MAPK signaling.

Long noncoding RNAs (lncRNAs) play important roles in regulating diverse cellular processes in the vessel wall, including atherosclerosis. RNA-Seq profiling of intimal lesions revealed a lncRNA, VINAS (Vascular INflammation and Atherosclerosis lncRNA Sequence), that is enriched in the aortic intima and regulates vascular inflammation. Aortic intimal expression of VINAS fell with atherosclerotic progression and rose with regression. VINAS knockdown reduced atherosclerotic lesion formation by 55% in LDL receptor–deficient (LDLR–/–) mice, independent of effects on circulating lipids, by decreasing inflammation in the vessel wall. Loss- and gain-of-function studies in vitro demonstrated that VINAS serves as a critical regulator of inflammation by modulating NF-κB and MAPK signaling pathways. VINAS knockdown decreased the expression of key inflammatory markers, such as MCP-1, TNF-α, IL-1β, and COX-2, in endothelial cells (ECs), vascular smooth muscle cells, and bone marrow–derived macrophages. Moreover, VINAS silencing decreased expression of leukocyte adhesion molecules VCAM-1, E-selectin, and ICAM-1 and reduced monocyte adhesion to ECs. DEP domain containing 4 (DEPDC4), an evolutionary conserved human ortholog of VINAS with approximately 74% homology, showed similar regulation in human and pig atherosclerotic specimens. DEPDC4 knockdown replicated antiinflammatory effects of VINAS in human ECs. These findings reveal a potentially novel lncRNA that regulates vascular inflammation, with broad implications for vascular diseases.

Sirt6 regulates autophagy in AGE-treated endothelial cells via KLF4

Abstract Aims To explore Sirt6 regulating autophagy in endothelial cells and the specific mechanism of this function with involvement of KLF4. Materials and methods Human umbilical vein endothelial cells were cultured with advanced glycation end products (AGE) treatment. Adv-Sirt6, LV-Sirt6 and LV-KLF4 were used to knockup Sirt6 and knockdown Sirt6 and KLF4 respectively. qPCR and Western Blotting were used to detect the mRNA and protein expression of Sirt6 and KLF4. Laser scanning confocal microscope was used to observe the LC3-II marked autophagosomes. Wildlife BALB/c mice were treated with STZ to produce diabetic mice model. AAV-Sirt6 was injected by tail vein injection to achieve Sirt6 knockdown. HE staining and scanning electron microscope were used to observe the aortic intima condition and autophagosomes number respectively. Results In AGE treated HUVECs, knockdown of Sirt6 led to impaired autophagy level along with less expression of autophagic markers LC3-II, Beclin-1, Lamp2 and autophagic marker p62. Knockdown and knockup of Sirt6 directly affected KLF4 expression level but KLF4 didn't have any effect on Sirt6 expression. Knockout of KLF4 offset the augmented autophagy caused by overexpression of Sirt6. In high-fat fed diabetic mice, downregulation of Sirt6 led to better cardiac function along with less autophagosomes and impaired aortic intima integrity. Conclusions Sirt6 improves autophagy both in vivo and in vitro and Sirt6 regulates autophagy via KLF4 in HUVECs. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Natural Science Foundation of China

A Case of Circumferential Type A Aortic Dissection with Intimo-Intimal Intussusception.

An 83-year-old woman was referred to our hospital under a diagnosis of acute aortic dissection. Contrast-enhanced computed tomography revealed no intimal flap in the mid-ascending aorta, and the intimal flap was found from the distal ascending aorta to the aortic arch. Operative findings showed that the intima of the mid-ascending aorta was circumferentially dissected and was inverted into the aortic arch. An emergent replacement of the ascending aorta was successfully performed; however, she died of a global intestinal ischemia on the fourth operative day.

Effect of cholesterol- and palm oil-enriched diets on rabbit aorta and aortic valve calcification

Atherosclerosis and calcific aortic valvular disease share a number of risk factors. Among them, hypercholesterolemia promotes atherosclerosis. However, whether a cholesterol-rich diet induces aortic valve calcification remains unclear. The effect of palm oil on vascular and valvular calcification is unknown. To study and compare the effects of cholesterol- and palm oil-enriched diets on aorta and aortic valve calcification in a rabbit model. New Zealand White rabbits were fed for 16 weeks with cholesterol- (0.3% cholesterol, n = 7) or palm oil-enriched diet (5% palm oil, n = 6) supplemented with vitamin D2 (25,000U/day/2.5 kg). Computed tomography (CT) was performed at regular intervals. Heart and aorta were collected for histological analyses. The cholesterol-rich diet provoked aortic atherosclerosis. It also induced a 2-fold increase of the aortic valve area compared to rabbits fed with a regular chow diet, with cell and lipid accumulation in the fibrosa. All rabbits displayed calcification of the aortic wall detectable in vivo by CT in 2 rabbits out of 7. Histology revealed calcification in the aortic valve of 4 rabbits out of 7 and thickening of valvular fibrosa. In contrast to the cholesterol-rich diet, the palm oil-rich diet did not lead to thickened aortic intima or aortic valve nor lipid accumulation. Interestingly, all rabbits treated with palm-oil enriched diet exhibited massive aortic wall calcification, characterized by the presence of large calcification nodules in the aortic media detectable in vivo by CT in 5 rabbits out of 6. Calcification was also found in the aortic valve fibrosa of 3 rabbits out of 6 and extracellular matrix remodeling was observed around the calcification nodules of the aortic media. Both diets induced histological changes and calcification of the aorta and aortic valve. However, the lesions differed between the two diets, suggesting different pathophysiological mechanisms.

Limited proliferation capacity of aortic intima resident macrophages requires monocyte recruitment for atherosclerotic plaque progression.

Early atherosclerosis depends upon responses by immune cells resident in the intimal aortic wall. Specifically, the healthy intima is thought to be populated by vascular dendritic cells (DC) that, during hypercholesterolemia, initiate atherosclerosis by being the first to accumulate cholesterol. Whether these cells remain key players in later stages of disease is unknown. Using murine lineage tracing models and gene expression profiling, we reveal that myeloid cells present in the intima of the aortic arch are not DCs but instead specialized aorta intima resident macrophages (MacAIR) that depend upon Csf-1 and sustained by local proliferation. Although MacAIR comprise the earliest foam cells in plaques, their proliferation during plaque progression is limited. After months of hypercholesterolemia, their presence in plaque is overtaken by recruited monocytes, which induce MacAIR-defining genes. These data redefine the lineage of intimal phagocytes and suggest that proliferation is insufficient to sustain generations of macrophages during plaque progression.

Non-coding RNAs in aortic dissection: From biomarkers to therapeutic targets.

Aortic dissection (AD) is the rupture of the aortic intima, causing the blood in the cavity to enter the middle of the arterial wall. Without urgent and proper treatment, the mortality rate increases to 50% within 48 hours. Most patients present with acute onset of symptoms, including sudden severe pain and complex and variable clinical manifestations, which can be easily misdiagnosed. Despite this, the molecular mechanisms underlying AD are still unknown. Recently, non‐coding RNAs have emerged as novel regulators of gene expression. Previous studies have proven that ncRNAs can regulate several cardiovascular diseases; therefore, their potential as clinical biomarkers and novel therapeutic targets for AD has aroused widespread interest. To date, several studies have reported that microRNAs are crucially involved in AD progression. Additionally, several long non‐coding RNAs and circular RNAs have been found to be differentially expressed in AD samples, suggesting their potential roles in vascular physiology and disease. In this review, we discuss the functions of ncRNAs in AD pathophysiology and highlight their potential as biomarkers and therapeutic targets for AD. Meanwhile, we present the animal models previously used for AD research, as well as the specific methods for constructing mouse or rat AD models.

Feasibility of intraoperative aortic root imaging in congenital heart surgery.

Intraoperative vascular imaging is a useful tool to evaluate coronary ostia in congenital heart patients with suboptimal preoperative imaging findings. Additionally, vascular imaging has potential value for visualization of the ascending aortic intima media thickness (IMT) in certain clinical scenarios. This study sought to evaluate the feasibility of intraoperative vascular imaging of coronary ostia and IMT during congenital heart surgery. We describe the technique for performance of intraoperative vascular imaging by a pediatric cardiologist using a high-resolution linear sequential array transducer. Intraoperative vascular imaging was obtained on seven patients. Coronary ostia were normal in all except one. This patient had congenital stenosis of the left coronary ostium discovered during intraoperative imaging and confirmed by the surgeon. In another patient with Williams syndrome, the IMT was noted to be prominent. It is feasible to perform intraoperative vascular imaging in less than 5minutes of operator's time and provides superior visualization of the coronary ostia and IMT.

Gypenoside Inhibits Endothelial Cell Apoptosis in Atherosclerosis by Modulating Mitochondria through PI3K/Akt/Bad Pathway.

Atherosclerosis remains the most common cause of deaths worldwide. Endothelial cell apoptosis is an important process in the progress of atherosclerosis, as it can cause the endothelium to lose their capability in regulating the lipid homeostasis, inflammation, and immunity. Endothelial cell injury can disrupt the integrity and barrier function of an endothelium and facilitate lipid deposition, leading to atherogenesis. Chinese medicine techniques for preventing and treating atherosclerosis are gaining attention, especially natural products. In this study, we demonstrated that gypenoside could decrease the levels of serum lipid, alleviate the formation of atherosclerotic plaque, and lessen aortic intima thickening. Gypenoside potentially activates the PI3K/Akt/Bad signal pathway to modulate the apoptosis-related protein expression in the aorta. Moreover, gypenoside downregulated mitochondrial fission and fusion proteins, mitochondrial energy-related proteins in the mouse aorta. In conclusion, this study demonstrated a new function of gypenoside in endothelial apoptosis and suggested a therapeutic potential of gypenoside in atherosclerosis associated with apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway.

Circulating chemerin level may be associated with early vascular pathology in obese children without overt arterial hypertension - preliminary results.

Background Elevated chemerin level is observed in patients with arterial hypertension. The aim of the study was to determine the relationship between chemerin level, and parameters of blood pressure and arterial stiffness in children and adolescents with obesity but without arterial hypertension. Methods In 23 children with obesity (13 girls, mean age 9.3, SD 1.9, mean BMI SDS 3.9, SD 1.7) 24h ABPM (Spacelabs 90,217, USA), common carotids and abdominal aorta intima media thickness measurements (Voluson 730, GE Medical System 8.5 and 3.5MHz probes), body composition analysis (Tanita BC 418SMA, Tokyo, Japan) were performed. Glucose, triglycerides, total, LDL and HDL cholesterol, liver enzymes, uric acid, creatinine, sodium, insulin and chemerin levels were assessed in blood sample taken after a 12-h fasting period. Results There was a significant correlation of circulating chemerin level with systolic blood pressure load in ABPM (r=0.5, p<0.05). Conclusion Elevated chemerin level may be associated with increased systolic blood pressure in obese children.

Rosuvastatin protects against endothelial cell apoptosis in vitro and alleviates atherosclerosis in ApoE-/- mice by suppressing endoplasmic reticulum stress.

The development of abnormal lipid-induced atherosclerosis is initiated with endothelial cell apoptosis. Vascular endothelial cells possess highly developed endoplasmic reticulum (ER), which is involved in lipid metabolism, indicating that ER stress may contribute chiefly to the induction of endothelial cell apoptosis. Based on its ability to reduce cholesterol levels, rosuvastatin may play an endothelial and vascular protective role by regulating ER stress. In the present study, the involvement of the inhibition of the ER stress-induced endothelial injury was investigated in combination with the lipid lowering effects of rosuvastatin. This compound can be used to inhibit cholesterol synthesis in atherosclerosis. Rosuvastatin decreased the apoptotic rates of human umbilical vascular endothelial cells (HUVECs) that had been stimulated with ox-low density lipoprotein (LDL) in vitro and repressed the mRNA levels of CHOP, sXBP1 and caspase-12, and decreased caspase-12 activity, as well as the content of glucose-regulated protein 78 (GRP78), phosphorylated (p)-protein kinase RNA-like ER kinase (PERK), p-inositol-requiring protein 1α (IRE1α) and p-eIF2α proteins. In addition, ApoE-/- mice were fed with atherogenic chow for 8 weeks for atherosclerosis induction and rosuvastatin was provided by intragastric administration for an additional 4 weeks. Subsequently, the atherosclerotic plaque formation in the aorta was evaluated by Oil Red O and hematoxylin and eosin staining, and the serum LDL, high-density lipoprotein, total cholesterol (TC) and triacylglycerol (TG) levels were measured. In addition, the induction of apoptosis of endothelial cells and the expression levels of GRP78, p-PERK, p-IRE1α and p-eIF2α were assessed in the aorta. Rosuvastatin repressed atherosclerotic plaque formation and endothelial apoptosis in the aorta and decreased LDL and TG levels in the serum, as determined by in vivo results. Furthermore, it downregulated the expression levels of protein chaperone GRP78, p-PERK, p-IRE1α and p-eIF2α in the aortic intima. The data indicated that rosuvastatin could protect HUVECs from ER stress-induced apoptosis triggered by oxidized LDL. It could also inhibit atherosclerosis formation in ApoE-/- mice aorta by regulating the PERK/eIF2α/C/EBPα-homologous protein and IRE1α/sXBP1 signaling pathways. Taken collectively, the present study demonstrated the preventive and therapeutic effects of rosuvastatin in protecting from the development of endothelial cell dysfunction diseases.

Alterations of aorta intima and media transcriptome in swine fed high-fat diet over 1-year follow-up period and of the switch to normal diet

Background and aimWe previously showed that 12-month high-fat diet (HFD) in pigs led to fattening and increased artery intima-media-thickness, which were partly reversed after 3-month return to control diet (CD). The aim of this study was to decipher underlying mechanism of action by using transcriptomic analyses of intima and media of aorta. Methods and resultsThirty-two pigs were divided into three groups: CD for 12 months; HFD for 12 months; switch diet group (regression diet; RD): HFD for 9 months followed by CD for 3 months. After 12 months, RNA was isolated from aorta intima and media for nutrigenomic analyses. HFD significantly affected gene expression in intima, while RD gene expression profile was distinct from the CD group. This suggests that switch to CD is not sufficient to correct gene expression alterations induced by HFD but counteracted expression of a group of genes. HFD also affected gene expression in media and as for intima, the expression profile of media of pigs on RD differed from that of these on CD. ConclusionsThis study revealed nutrigenomic modifications induced by long-term HFD consumption on arterial intima and media. The return to CD was not sufficient to counteract the genomic effect of HFD.

Aortic angioscopy assisted thoracic endovascular repair for chronic type B aortic dissection

BackgroundNon-obstructive general angioscopy is a powerful modality for detecting areas in the aorta with vulnerable plaque, which are difficult to visualize using conventional diagnostic tools such as computed tomography (CT). The aim of the present study was to clarify the efficacy and usefulness of aortic angioscopy in patients with chronic type B aortic dissection scheduled for thoracic endovascular repair (TEVAR). MethodsTen patients with chronic type B aortic dissection who underwent elective TEVAR were enrolled. Before starting the stent graft procedure, the aortic intima was observed by use of non-obstructive general angioscopy. Based on those findings, the range of the stent graft position was confirmed. ResultsIn all patients, observations of the aortic intima with non-obstructive general angioscopy from a point just proximal of the descending aorta to the iliac artery were successful. At the proximal site, an entry site or ulcer-like projection was detected in all patients, while a small intimal tear or entry, or an irregular intima surface with a salmon-pink color were seen in some cases. In contrast, preoperative CT did not detect any such findings in the same locations. After confirming the position of the abnormal intima, we determined the position of the distal end of the stent graft. No complications considered to be related to aortic angioscopy were noted. ConclusionsNon-obstructive general angioscopy is useful for observing the condition of the aortic intima, revealing abnormal conditions, and confirming a normal aortic intima in patients with chronic type B aortic dissection. This modality may play an important role in determining the precise position of a stent graft for a TEVAR procedure.