Myeloid cell microsomal prostaglandin E synthase-1 fosters atherogenesis in mice

Microsomal prostaglandin E synthase-1 (mPGES-1) in myeloid and vascular cells differentially regulates the response to vascular injury, reflecting distinct effects of mPGES-1–derived PGE₂ in these cell types on discrete cellular components of the vasculature. The cell selective roles of mPGES-1 in atherogenesis are unknown. Mice lacking mPGES-1 conditionally in myeloid cells (Mac-mPGES-1-KOs), vascular smooth muscle cells (VSMC-mPGES-1-KOs), or endothelial cells (EC-mPGES-1-KOs) were crossed into hyperlipidemic low-density lipoprotein receptor-deficient animals. En face aortic lesion analysis revealed markedly reduced atherogenesis in Mac-mPGES-1-KOs, which was concomitant with a reduction in oxidative stress, reflective of reduced macrophage infiltration, less lesional expression of inducible nitric oxide synthase (iNOS), and lower aortic expression of NADPH oxidases and proinflammatory cytokines. Reduced oxidative stress was reflected systemically by a decline in urinary 8,12-iso-iPF_2α-VI. In contrast to exaggeration of the response to vascular injury, deletion of mPGES-1 in VSMCs, ECs, or both had no detectable phenotypic impact on atherogenesis. Macrophage foam cell formation and cholesterol efflux, together with plasma cholesterol and triglycerides, were unchanged as a function of genotype. In conclusion, myeloid cell mPGES-1 promotes atherogenesis in hyperlipidemic mice, coincident with iNOS-mediated oxidative stress. By contrast, mPGES-1 in vascular cells does not detectably influence atherogenesis in mice. This strengthens the therapeutic rationale for targeting macrophage mPGES-1 in inflammatory cardiovascular diseases.Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce pain and inflammation by suppressing the formation of proinflammatory prostaglandins (PGs), particularly prostaglandin E₂ (PGE₂) formed by cyclooxygenase-2 (COX-2) (1). However, the development of NSAIDs specific for inhibition of COX-2 revealed a cardiovascular hazard attributable to suppression of cardioprotective PGs, especially prostacyclin (PGI₂) (2). This risk appears to extend to some of the older NSAIDs, like diclofenac, that also inhibit specifically COX-2 (3, 4). These developments prompted interest in microsomal PGE synthase (mPGES)-1 as a downstream alternative drug target to COX-2 (5): it is the dominant source among PGES enzymes in the biosynthesis of PGE₂ (6). Unlike NSAIDs, inhibitors of mPGES-1 would spare PGI₂ from suppression. Indeed, blockade or deletion of mPGES-1 results in accumulation of its PGH₂ substrate, rendering it available for metabolism by other PG synthases, including PGI₂ synthase (PGIS) (7).Consistent with these observations, we have found that whereas deletion of COX-2 in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) renders mice susceptible to thrombosis and hypertension (2), deletion of mPGES-1 in vascular cells has no such effect (8). Indeed, global deficiency of mPGES-1 restrains atherogenesis (9), the proliferative response to vascular injury (10) and angiotensin-induced aortic aneurysm formation (11) in mice.Despite this attractive cardiovascular profile, mPGES-1 is a complex drug target. The dominant prostanoid products of substrate rediversion differ among cell types. For example, whereas PGI₂ might be augmented in vascular cells, the consequence of mPGES-1 blockade in other cells might be an increase in thromboxane (Tx)A₂, a PG that promotes platelet activation, vasoconstriction, and atherogenesis (9). Even if an increase in PGI₂ afforded a desirable cardiovascular profile, it might undermine the analgesic efficacy of mPGES-1 inhibitors. Although the impacts of global deletion of mPGES-1 and COX-2 in many mouse models of analgesia are indistinguishable (12, 13), in some, PGI₂ rather than PGE₂ predominates (14) and thus may be the dominant mediator in certain subtypes of human pain. Finally, the consequences of PGE₂ suppression might differ between cell types. PGE₂ activates four E prostanoid (EP) receptors with contrasting intracellular signaling and consequent biology (15, 16). Indeed, the contrasting effect of mPGES-1 deletion in myeloid vs. vascular cells on the proliferative response to vascular injury reflects the differential consequences of EP activation rather than substrate rediversion (8).A potentially discriminating feature among inhibitors of COX-2 and mPGES-1 is their effect on atherosclerosis. Global postnatal deletion of COX-2 accelerates atherogenesis in hyperlipidemic mice (17), an observation that accords with a similar effect of deleting the PGI₂ receptor (the IP) (18, 19) and with the delayed detection of a cardiovascular hazard in randomized trials of COX-2 inhibitors in patients initially selected for being at low cardiovascular risk (20). By contrast, global deletion of mPGES-1 restrains atherogenesis in mice; in this case suppression of PGE₂ coincides with an increase in biosynthesis of PGI₂ (9). Here, we wished to segregate the effects on atherosclerosis of mPGES-1 depletion in myeloid from vascular cells. Our results strengthen the rationale for targeting macrophage mPGES-1 in the treatment of inflammatory cardiovascular disease.     

内皮祖细胞与粥样斑块稳定性研究进展

动脉粥样硬化是最常见的和最具危害性的疾病,给人民健康带来很大威胁,而粥样斑块内滋养血管新生,加重斑块负担,使斑块由稳定状态转变为不稳定状态,增加患者发生急性心肌梗死、脑卒中等的风险。由骨髓衍生的内皮祖细胞,促进再内皮化恢复血管受损内皮的完整性,同时增加缺血缺氧部位的血管新生,对粥样斑块形成及发展均产生影响。因此现将重点探讨内皮祖细胞与滋养血管的关系及对动脉粥样硬化斑块稳定性的影响。     

关注致动脉粥样硬化的非传统危险因素

动脉硬化是指动脉管壁的增厚、变硬和弹性减低。动脉粥样硬化是动脉硬化的特定类型,指动脉管壁由于钙和脂肪物质在管壁堆积而变厚。尽管对动脉粥样硬化的发病机制至今尚未完全明了,但有较明确的原因即动脉粥样硬化的危险因素,包括传统和非传统危险因素,我们对传统危险因素已逐步认识。随着对血管危险因素的再认识,非传统危险因素开始被关注,这将对血管早期风险评价提供依据。现就非传统危险因素对动脉粥样硬化性血管病变的影响进行阐述。     

花生四烯酸代谢产物与动脉粥样硬化

随着心脑血管疾病发病率的逐年增高,动脉粥样硬化已成为医学研究的重点和热点。近年研究发现,花生四烯酸的代谢产物在动脉粥样硬化的发生、发展及斑块不稳定性中发挥着重要作用,并有望为动脉粥样硬化的防治提供新思路。现就花生四烯酸代谢产物与动脉粥样硬化之间的关系做一综述。     

多巴胺受体与动脉粥样硬化

内皮细胞损伤,血液循环中的单核细胞迁移到内皮下分化为巨噬细胞,巨噬细胞及血管平滑肌细胞吞噬化学修饰的脂蛋白转变为泡沫细胞,巨噬细胞和平滑肌细胞的迁移、增生及炎症因子的释放等过程被认为是动脉粥样硬化的主要病理生理过程。多巴胺受体可以通过影响平滑肌细胞、内皮细胞的功能等直接或间接参与动脉粥样硬化的上述病理生理过程,对动脉粥样硬化具有保护作用。现探讨多巴胺受体在动脉粥样硬化这一病理生理过程中的作用。     

Orthopedic management of the extremities in patients with Morquio A syndrome

Background

Musculoskeletal involvement in Morquio A syndrome (mucopolysaccharidosis IVA; MPS IVA) contributes significantly to morbidity and mortality. While the spinal manifestations of the disorder have received considerable attention in the literature, there have been few reported studies to date to guide the management of the orthopedic problems associated with the lower and upper extremities.

Purpose

The objective was to develop recommendations for the management of the extremities in patients with Morquio A syndrome.

Methods

A group of specialists in orthopedics, pediatrics and genetics with experience in the management of Morquio A patients convened to review and discuss current clinical practices and to develop preliminary recommendations. Evidence from the literature was retrieved. Recommendations were further refined until consensus was reached.

Results and conclusions

This present article provides a detailed review and discussion of the lower and upper extremity deformities in Morquio A syndrome and presents recommendations for the assessment and treatment of these complications. Key issues, including the importance of early diagnosis and the implications of medical therapy, are also addressed. The recommendations herein represent an attempt to develop a uniform and practical approach to managing patients with Morquio A syndrome and improving their outcomes.     

Vitamin D insufficiency and subclinical atherosclerosis in non-diabetic males living with HIV

Introduction

Vitamin D insufficiency (VDI) has been associated with increased cardiovascular risk in the non-HIV population. This study evaluates the relationship among serum 25-hydroxyvitamin D [25(OH)D] levels, cardiovascular risk factors, adipokines, antiviral therapy (ART) and subclinical atherosclerosis in HIV-infected males.

Methods

A cross-sectional study in ambulatory care was made in non-diabetic patients living with HIV. VDI was defined as 25(OH)D serum levels <75 nmol/L. Fasting lipids, glucose, inflammatory markers (tumour necrosis factor-α, interleukin-6, high-sensitivity C-reactive protein) and endothelial markers (plasminogen activator inhibitor-1, or PAI-I) were measured. The common carotid artery intima-media thickness (C-IMT) was determined. A multivariate logistic regression analysis was made to identify factors associated with the presence of VDI, while multivariate linear regression analysis was used to identify factors associated with common C-IMT.

Results

Eighty-nine patients were included (age 42±8 years), 18.9% were in CDC (US Centers for Disease Control and Prevention) stage C and 75 were on ART. VDI was associated with ART exposure, sedentary lifestyle, higher triglycerides levels and PAI-I. In univariate analysis, VDI was associated with greater common C-IMT. The multivariate linear regression model, adjusted by confounding factors, revealed an independent association between common C-IMT and patient age, time of exposure to protease inhibitors (PIs) and impaired fasting glucose (IFG). In contrast, there were no independent associations between common C-IMT and VDI or inflammatory and endothelial markers.

Conclusions

VDI was not independently associated with subclinical atherosclerosis in non-diabetic males living with HIV. Older age, a longer exposure to PIs, and IFG were independent factors associated with common C-IMT in this population.     

Motion analysis of the upper extremity in children with unilateral cerebral palsy—An assessment of six daily tasks

Restrictions in range of motion of the upper extremity are common in patients with unilateral cerebral palsy (CP). The purpose of this study was to investigate movement deviations of the upper extremity in children with unilateral CP by means of 3D motion capture as well as by the use of easy to use scores and questionnaires (MACS, MRC, MAS, ABILHAND-Kids). 16 children with a spastic, unilateral CP were included and compared to a group of 17 typically developing adolescents (TD). The movement time and range of motion (ROM) of six uni- and bimanual daily tasks were compared and correlated with the scores and questionnaires. Movement times increased significantly with involvement according to MACS in all tasks. The restrictions in ROM were pronounced in the forearm. As a compensatory mechanism the children of the MACS 2 and 3 groups showed increased trunk movement. Furthermore, there was a positive correlation between the MACS and the ABILHAND-Kids Questionnaire. In contrast to previous studies, which reported a correlation between the restrictions in ROM and the MACS, this study showed no consistent correlation between the restrictions in ROM neither with the MACS nor with the ABILHAND-Kids. While the MACS and the ABILHAND-Kids function as a simple rating tool for clinical use, the detailed analysis of different daily tasks using 3-D-motion capture provides more detailed information about the movement deviations and spatiotemporal parameters.