端粒生物学与胸主动脉瘤的研究进展

摘要：随着细胞生理性衰老,端粒（telomere）即染色体末端的重复性 DNA 序列会出现累积性损伤,而血管内皮细胞、平滑肌细胞衰老相关的端粒损伤和修复则被认为是退行性血管疾病发病的分子机制之一。胸主动脉瘤为老年人群中的重要致死性疾病之一,与衰老相关的退行性变在其中发挥着重要的作用。因此本文主要对端粒/端粒酶在胸主动脉瘤发病和进展中的作用做了概述,总结了血管病理学中端粒/端粒酶的调控机制。     

血管内皮细胞在主动脉瘤发展中作用的研究进展

主动脉瘤(aortic aneurysm)是以动脉出现永久性扩张为特征的一类血管疾病，常发生于肾下以及胸近端区域，破裂后十分凶险。目前主动脉瘤的治疗方式局限于手术干预，且尚未发现有效治疗药物，因此，寻找有效的干预靶点成为主动脉瘤治疗的新思路。近年来的研究表明，血管内皮细胞(endothelial cell)在受到外界环境刺激后可发生氧化应激、炎症反应及屏障功能破坏，而这些均可能参与动脉瘤的发生发展。随着内皮细胞在动脉瘤中的重要作用逐渐被揭示，基于内皮细胞为靶点进行干预也取得了较多的研究进展。本文重点综述了内皮细胞在主动脉瘤发生发展中的具体作用机制及以内皮细胞为靶点的动脉瘤治疗方法，旨在为临床干预主动脉瘤进程提供参考。     

血管外膜在动脉粥样硬化中的作用

动脉粥样硬化被认为是受损的内皮细胞释放粘附因子,吸引单核细胞粘附浸润到内膜下吞噬脂质,同时平滑肌细胞进行增殖迁移并形成新生内膜的过程,但目前越来越多的证据提示血管外膜作为反应的先导者从外向内参与了这一过程。在诸多血管疾病模型中,均能检测到外膜的早期激活。成纤维细胞作为血管外膜的主要细胞成分,在血管损伤早期会进行增殖迁移至中膜和内膜,还可以通过释放活性氧、各种细胞因子、基质金属蛋白酶等来影响炎症反应,导致内膜增生,最终促进了血管重塑及一些心血管疾病的发生。因此,越来越多的研究关注外膜成纤维细胞对于动脉粥样硬化、糖尿病、腹主动脉瘤等疾病中的作用及其机制,本文对该领域新近研究进展做一综述。     

自噬对血管功能的影响及与相关疾病的关联研究进展

自噬(autophagy)是细胞利用溶酶体降解自身受损的细胞器和大分子物质的过程,在稳定细胞内环境中发挥着重要作用．研究发现,自噬影响血管功能,与血管疾病的病理生理进程密切相关．本文从自噬对血管功能的影响,与血管相关疾病(如动脉粥样硬化、腹主动脉瘤、肺动脉高压、糖尿病血管并发症等)的关系及药物对血管壁细胞自噬的调控进行综述,希望从自噬的角度来了解血管的功能和病变及一些疾病的发生发展进程,为治疗血管相关疾病提供新的思路．     

未折叠蛋白质与感染、炎症和癌症

未折叠蛋白(Unfolded proteins,UP)是蛋白质质量控制的对象,其可诱发UP应答(UPR),介导细胞死亡或炎症反应。在多种感染、炎症和癌症疾病中,病原体或恶性转化细胞可劫持UPR,在避免细胞死亡的前提下,介导慢性炎症反应,从而起到促进疾病发生发展的作用。这种UP相关炎症与疾病进展之间的机制联系目前不清楚,且研究技术手段缺乏。本文对UP与感染、炎症和癌症的关系以及UP蛋白质组学研究技术的进展进行综述,核心目的是总结上述领域最新研究思路,并促进以UP为靶向的生物学和疾病推动的科学研究。     

自噬与小胶质细胞相关神经炎症

小胶质细胞是中枢神经系统中重要的神经免疫细胞,当中枢神经系统受到刺激后,小胶质细胞通过炎症反应来应对这种刺激,这种炎症反应在神经性疾病中具有重要作用。研究发现,小胶质细胞自噬在炎症的发生与发展中也发挥了重要作用,它能直接或间接地影响炎症反应,同时自身也被其他信号调控。自噬过程有利有弊,适当的自噬过程能促进疾病的恢复,自噬紊乱则使病情恶化,所以明确自噬的调控机制对治疗和预防相关疾病具有重要意义。本文综述了近年来自噬在小胶质细胞相关炎症中研究进展,以及其可能的调控机制,以期为相关研究人员提供一定帮助。     

血管内皮细胞衰老与血管疾病

细胞衰老是指细胞在各种应激条件下出现周期阻滞,不可逆地丧失增殖能力,其形态、基因表达和功能都发生特定变化的过程。研究表明,血管内皮细胞衰老可以通过削弱血管功能,促进衰老相关血管疾病的发生发展。然而,有关内皮细胞衰老的发生机制以及内皮细胞衰老影响血管功能及衰老相关血管疾病的潜在机制尚待挖掘。本文从血管内皮细胞衰老相关的信号通路,以及血管内皮细胞衰老与血管功能和血管相关疾病（动脉粥样硬化、高血压和糖尿病血管并发症）的最新研究进展进行综述,为进一步认识血管疾病的发病机制,延缓血管衰老提供新的思路。     

NLRP3炎症小体在脂肪组织纤维化中的作用及运动干预研究进展

脂肪组织纤维化是指白色脂肪组织细胞外基质的过度沉积，是代谢功能障碍的重要诱因，探究其发生机理对代谢相关疾病的防治意义重大。研究表明，NLRP3炎症小体与脂肪组织纤维化关联密切，但其机制尚未完全厘清。作为一种防治慢病的有效策略，运动可通过抑制NLRP3炎症小体活化减轻炎症反应，从而缓解炎症相关疾病的发生与发展。本文就NLRP3炎症小体的生物学特性以及与脂肪组织纤维化的关系进行归纳梳理，总结分析运动通过NLRP3炎症小体调节脂肪组织纤维化的可能机理，以期为脂肪组织炎症相关疾病的防治提供理论参考依据。     

干眼症的免疫调节机制及相关治疗新进展

干眼症是目前最常见的眼表疾病,它可以导致眼部不适,甚至引起视力障碍,它极大地影响了患者的工作和生活质量,随着干眼症的发病率逐年升高,该病越来越受到人们的重视,已成为当今眼科研究热点之一。干眼症病因繁多、发病机制复杂,近年来随着对该病病因、发病机制及治疗等方面的深入研究,研究学者认为免疫调节是其主要机制之一,眼表的非特异性免疫反应和特异性免疫反应共同进行调节,目前已发现多种免疫细胞以及炎症因子参与了干眼症的发生发展。干眼症治疗的常规方法是应用有润滑眼表作用的人工泪液,但对于中重度干眼症,不可只是单纯的缓解症状,还应加以抗炎药物治疗其根本。本文主要针对干眼症的免疫调节机制以及相关治疗的最新研究进展加以综述。     

炎症反应中巨噬细胞的力学生物学

炎症反应存在于机体诸多生理和病理过程中,是最基本的保护性反应之一。在动脉粥样硬化等慢性炎症性血管疾病发病过程中,巨噬细胞作为重要的免疫细胞参与并调控炎症的进程。在炎症刺激下,巨噬细胞的生物力学特性(如质膜流动性、细胞刚度、细胞与基质的粘附、细胞骨架的组成与结构等)会发生相应的变化,细胞行为和功能随之改变。本文旨在回顾炎症模型下巨噬细胞力学特性与其功能之间关系及其机理的研究进展,尤其关注了细胞刚度如何介导炎症刺激对巨噬细胞行为和功能的影响。     

Cyclooxygenase-2 Inhibition Attenuates Abdominal Aortic Aneurysm Progression in Hyperlipidemic Mice

Abdominal aortic aneurysms (AAAs) are a chronic inflammatory disease that increase the risk of life-threatening aortic rupture. In humans, AAAs have been characterized by increased expression of cyclooxygenase-2 and the inactivation of COX-2 prior to disease initiation reduces AAA incidence in a mouse model of the disease. The current study examined the effectiveness of selective cyclooxygenase-2 (COX-2) inhibition on reducing AAA progression when administered after the initiation of AAA formation. AAAs were induced in hyperlipidemic apolipoprotein E-deficient mice by chronic angiotensin II (AngII) infusion and the effect of treatment with the COX-2 inhibitor celecoxib was examined when initiated at different stages of the disease. Celecoxib treatment that was started 1 week after initiating AngII infusion reduced AAA incidence by 61% and significantly decreased AAA severity. Mice treated with celecoxib also showed significantly reduced aortic rupture and mortality. Treatment with celecoxib that was started at a late stage of AAA development also significantly reduced AAA incidence and severity. Celecoxib treatment significantly increased smooth muscle alpha-actin expression in the abdominal aorta and did not reduce expression of markers of macrophage-dependent inflammation. These findings indicate that COX-2 inhibitor treatment initiated after formation of AngII-induced AAAs effectively reduces progression of the disease in hyperlipidemic mice.     

Abdominal aortic aneurysms: an autoimmune disease?

Abdominal aortic aneurysms (AAAs) are a multifactorial degenerative vascular disorder. One of the defining features of the pathophysiology of aneurysmal disease is inflammation. Recent developments in vascular and molecular cell biology have increased our knowledge on the role of the adaptive and innate immune systems in the initiation and propagation of the inflammatory response in aortic tissue. AAAs share many features of autoimmune disease, including genetic predisposition, organ specificity and chronic inflammation. Here, this evidence is used to propose that the chronic inflammation observed in AAAs is a consequence of a dysregulated autoimmune response against autologous components of the aortic wall that persists inappropriately. Identification of the molecular and cellular targets involved in AAA formation will allow the development of therapeutic agents for the treatment of AAA.     

Hypoperfusion of the Adventitial Vasa Vasorum Develops an Abdominal Aortic Aneurysm

The aortic wall is perfused by the adventitial vasa vasorum (VV). Tissue hypoxia has previously been observed as a manifestation of enlarged abdominal aortic aneurysms (AAAs). We sought to determine whether hypoperfusion of the adventitial VV could develop AAAs. We created a novel animal model of adventitial VV hypoperfusion with a combination of a polyurethane catheter insertion and a suture ligation of the infrarenal abdominal aorta in rats. VV hypoperfusion caused tissue hypoxia and developed infrarenal AAA, which had similar morphological and pathological characteristics to human AAA. In human AAA tissue, the adventitial VV were stenotic in both small AAAs (30–49 mm in diameter) and in large AAAs (> 50 mm in diameter), with the sac tissue in these AAAs being ischemic and hypoxic. These results indicate that hypoperfusion of adventitial VV has critical effects on the development of infrarenal AAA.     

Model studies of the flow in abdominal aortic aneurysms during resting and exercise conditions

Pulsatile flow in abdominal aortic aneurysm (AAA) models has been examined in order to understand the hemodynamics that may contribute to growth of an AAA. The model studies were conducted by experiments (flow visualization and laser Doppler velocimetry) and by numerical simulation using physiologically realistic resting and exercise flow conditions. We characterize the flow for two AAA model shapes and sizes emulating early AAA development through moderate AAA growth (mean and peak Reynolds numbers of 362<Re_mean<1053 and 3308<Re_peak<5696 with Womersley parameter 16.4<<21.2). The results of our investigation indicate that AAA flow can be divided into three flow regimes: (i) Attached flow over the entire cycle in small AAAs at resting conditions, (ii) vortex formation and translation in moderate size AAAs at resting conditions, and (iii) vortex formation, translation and turbulence in moderate size AAAs under exercise conditions. The second two regimes are classified in the medical literature as disturbed flow conditions that have been correlated with atherogenesis as well as thrombogenesis. Thus, AAA disturbed hemodynamics may be a contributing factor to AAA growth by accelerating the degeneration of the arterial wall. Our investigation also concluded that vortex development is considerably weaker in an asymmetric AAA. Furthermore, turbulence was not observed in the asymmetric model. Finally, our investigation suggests a new mode of transition to turbulence: vortex ring instability and bursting to turbulence. The transition process depends on a combination of the pulsatile flow conditions and the tube cross-sectional area change.     

Doxycycline Does Not Influence Established Abdominal Aortic Aneurysms in Angiotensin II-Infused Mice

Background

There is no proven medical approach to attenuating expansion and rupture of abdominal aortic aneurysms (AAAs). One approach that is currently being investigated is the use of doxycycline. Despite being primarily used as an antimicrobial drug, doxycycline has been proposed to function in reducing AAA expansion. Doxycycline is effective in reducing the formation in the most commonly used mouse models of AAAs when administered prior to the initiation of the disease. The purpose of the current study was to determine the effects of doxycycline on established AAAs when it was administered at a dose that produces therapeutic serum concentrations.

Methods and Results

LDL receptor −/− male mice fed a saturated-fat supplemented diet were infused with AngII (1,000 ng/kg/min) via mini-osmotic pumps for 28 days. Upon verification of AAA formation by noninvasive high frequency ultrasonography, mice were stratified based on aortic lumen diameters, and continuously infused with AngII while also administered either vehicle or doxycycline (100 mg/kg/day) in drinking water for 56 days. Administration of doxycycline led to serum drug concentrations of 2.3±0.6 µg/ml. Doxycycline administration had no effect on serum cholesterol concentrations and systolic blood pressures. Doxycycline administration did not prevent progressive aortic dilation as determined by temporal measurements of lumen dimensions using high frequency ultrasound. This lack of effect on AAA regression and progression was confirmed at the termination of the study by ex vivo measurements of maximal width of suprarenal aortas and AAA volumes. Also, doxycycline did not reduce AAA rupture. Medial and adventitial remodeling was not overtly changed by doxycycline as determined by immunostaining and histological staining.

Conclusions

Doxycycline administration did not influence AngII-induced AAA progression and aortic rupture when administered to mice with established AAAs.     

Numerical identification of the rupture locations in patient-specific abdominal aortic aneurysmsusing hemodynamic parameters

The rupture of an abdominal aortic aneurysm (AAA) is generally an unexpected event. Up to now, there is no agreement on an accurate criteria to predict the rupture risk of AAAs. This paper aims to numerically investigate the hemodynamics of three ruptured and one non-ruptured patient-specific AAA models to correlate local hemodynamic parameters with the rupture sites, and for the first time, this study introduced helicity as a potential index for the rupture potential of AAAs.3D reconstructions from CT scans were done. The simulation revealed that all the rupture sites were in regions of stagnation with near zero wall shear stress (WSS) but large WSS gradient (WSSG), which may explain the observation by the former researchers that the rupture site in the ruptured AAA has the lowest recorded wall thickness compared to other non-ruptured regions. Moreover, all the ruptures occurred at regions of zero helicity which represents a purely axial or circumferential flow. In addition, this study revealed that the double low region for the non-ruptured AAA was present with a thick layer of plaques, it suggests that the AAA rupture and the formation of atherosclerotic plaques may share a lot common physiological features. However, the fact that there are no plaques present in the walls of three RAAAs also indicates that AAA is not always a result of atherosclerosis. The current computational study may complement the maximum diameter, peak wall stress and other clinically relevant factors in AAA ruptures to identify the rupture sites of AAAs.     

Fluid structure interaction of patient specific abdominal aortic aneurysms: a comparison with solid stress models

Background  

Abdominal aortic aneurysm (AAA) is a dilatation of the aortic wall, which can rupture, if left untreated. Previous work has shown that, maximum diameter is not a reliable determinant of AAA rupture. However, it is currently the most widely accepted indicator. Wall stress may be a better indicator and promising patient specific results from structural models using static pressure, have been published. Since flow and pressure inside AAA are non-uniform, the dynamic interaction between the pulsatile flow and wall may influence the predicted wall stress. The purpose of the present study was to compare static and dynamic wall stress analysis of patient specific AAAs.     

Mechanical stresses in abdominal aortic aneurysms: influence of diameter, asymmetry, and material anisotropy

Biomechanical studies suggest that one determinant of abdominal aortic aneurysm (AAA) rupture is related to the stress in the wall. In this regard, a reliable and accurate stress analysis of an in vivo AAA requires a suitable 3D constitutive model. To date, stress analysis conducted on AAA is mainly driven by isotropic tissue models. However, recent biaxial tensile tests performed on AAA tissue samples demonstrate the anisotropic nature of this tissue. The purpose of this work is to study the influence of geometry and material anisotropy on the magnitude and distribution of the peak wall stress in AAAs. Three-dimensional computer models of symmetric and asymmetric AAAs were generated in which the maximum diameter and length of the aneurysm were individually controlled. A five parameter exponential type structural strain-energy function was used to model the anisotropic behavior of the AAA tissue. The anisotropy is determined by the orientation of the collagen fibers (one parameter of the model). The results suggest that shorter aneurysms are more critical when asymmetries are present. They show a strong influence of the material anisotropy on the magnitude and distribution of the peak stress. Results confirm that the relative aneurysm length and the degree of aneurysmal asymmetry should be considered in a rupture risk decision criterion for AAAs.     

Periostin Links Mechanical Strain to Inflammation in Abdominal Aortic Aneurysm

Aims

Abdominal aortic aneurysms (AAAs) are characterized by chronic inflammation, which contributes to the pathological remodeling of the extracellular matrix. Although mechanical stress has been suggested to promote inflammation in AAA, the molecular mechanism remains uncertain. Periostin is a matricellular protein known to respond to mechanical strain. The aim of this study was to elucidate the role of periostin in mechanotransduction in the pathogenesis of AAA.

Methods and Results

We found significant increases in periostin protein levels in the walls of human AAA specimens. Tissue localization of periostin was associated with inflammatory cell infiltration and destruction of elastic fibers. We examined whether mechanical strain could stimulate periostin expression in cultured rat vascular smooth muscle cells. Cells subjected to 20% uniaxial cyclic strains showed significant increases in periostin protein expression, focal adhesion kinase (FAK) activation, and secretions of monocyte chemoattractant protein-1 (MCP-1) and the active form of matrix metalloproteinase (MMP)-2. These changes were largely abolished by a periostin-neutralizing antibody and by the FAK inhibitor, PF573228. Interestingly, inhibition of either periostin or FAK caused suppression of the other, indicating a positive feedback loop. In human AAA tissues in ex vivo culture, MCP-1 secretion was dramatically suppressed by PF573228. Moreover, in vivo, periaortic application of recombinant periostin in mice led to FAK activation and MCP-1 upregulation in the aortic walls, which resulted in marked cellular infiltration.

Conclusion

Our findings indicated that periostin plays an important role in mechanotransduction that maintains inflammation via FAK activation in AAA.     

Long term stabilization of expanding aortic aneurysms by a short course of cyclosporine A through transforming growth factor-beta induction

Abdominal aortic aneurysms (AAAs) expand as a consequence of extracellular matrix destruction, and vascular smooth muscle cell (VSMC) depletion. Transforming growth factor (TGF)-beta 1 overexpression stabilizes expanding AAAs in rat. Cyclosporine A (CsA) promotes tissue accumulation and induces TGF -beta1 and, could thereby exert beneficial effects on AAA remodelling and expansion. In this study, we assessed whether a short administration of CsA could durably stabilize AAAs through TGF-beta induction. We showed that CsA induced TGF-beta1 and decreased MMP-9 expression dose-dependently in fragments of human AAAs in vitro, and in animal models of AAA in vivo. CsA prevented AAA formation at 14 days in the rat elastase (diameter increase: CsA: 131.9±44.2%; vehicle: 225.9±57.0%, P = 0.003) and calcium chloride mouse models (diameters: CsA: 0.72±0.14 mm; vehicle: 1.10±0.11 mm, P = .008), preserved elastic fiber network and VSMC content, and decreased inflammation. A seven day administration of CsA stabilized formed AAAs in rats seven weeks after drug withdrawal (diameter increase: CsA: 14.2±15.1%; vehicle: 45.2±13.7%, P = .017), down-regulated wall inflammation, and increased αSMA-positive cell content. Co-administration of a blocking anti-TGF-beta antibody abrogated CsA impact on inflammation, αSMA-positive cell accumulation and diameter control in expanding AAAs. Our study demonstrates that pharmacological induction of TGF-beta1 by a short course of CsA administration represents a new approach to induce aneurysm stabilization by shifting the degradation/repair balance towards healing.