Meng Ye

Retrograde popliteal approach for challenging occlusions of the femoral-popliteal arteries

OBJECTIVE Antegrade ipsilateral subintimal angioplasty for recanalization of the superficial femoral arteries (SFAs) has a failure rate of 10%-20%. We report our initial experiences performing recanalization of the SFA or popliteal artery (PA) in cases of failed antegrade angioplasty using a medial infracondylar retrograde popliteal approach with the patient supine. METHODS Between February 2010 and December 2011, 19 patients with chronic total occlusion of the SFA and/or proximal PA (mean occlusion length, 20.5 ± 5.54 cm) underwent transpopliteal procedures after failure of an antegrade procedure. Upon failure to re-enter the true lumen distal to the occlusion during initial antegrade recanalization with the patient supine, a medial retrograde popliteal access at the infracondylar plane was adopted, without turning the patient (with the leg in a 60° external rotation and the knee in a gentle flexion). Puncture of the distal PA was guided fluoroscopically and a guidewire was inserted into the true lumen, after which retrograde recanalization proceeded in accordance with standard protocol. Once the occlusion was crossed from distal to proximal, the wire was advanced through a 6F sheath in the common femoral artery. The preferred approach for angioplasty and stenting was from the femoral artery. Hemostasis at the popliteal access was achieved by combined intraluminal balloon dilatation and manual compression (3-5 minutes). The mean follow-up period was 8.6 ± 4.1 months and included measuring the ankle-brachial index and duplex ultrasound. RESULTS Technical success (puncture of the PA and SFA recanalization) was achieved in all cases. All but one patient received stent implantation from the antegrade approach. Sheaths were used in five (26%) patients; four patients were treated with a 4F sheath and one with a 6F sheath. There was one (5.26%) major complication (a popliteal access site occlusion) and two (10.5%) minor complications (small hematomas in the popliteal region). The primary patency at 6 months was 84.2%. CONCLUSIONS The medial infracondylar retrograde popliteal approach with the patient in the supine position can be considered safe and efficient for recanalization of the SFA or proximal PA after failure of an antegrade approach.

Downregulation of Pin1 in human atherosclerosis and its association with vascular smooth muscle cell senescence

Objective Pin1 is prevalently overexpressed in human cancers and implicated to regulate cell growth and apoptosis. Thus far, however, no role for Pin1 has been described in modulating vascular smooth muscle cell (VSMC) senescence. Methods Immunohistochemistry and Western blotting were used to assess Pin1 protein level in human normal and atherosclerotic tissues. &bgr;‐galactosidase staining, cumulative population doubling level, telomerase activity, and relative telomere length measurement were used to confirm VSMC senescence. The expressions of Pin1 and other genes involved in this research were analyzed by quantitative reverse‐transcription polymerase chain reaction and Western blotting in VSMCs. Apolipoprotein E gene‐deleted mice (ApoE−/−) fed a high‐fat diet were treated with juglone or 10% ethanol, respectively, for 3 weeks. The extent of atherosclerosis was evaluated by Oil Red O, Masson trichrome staining, and immunohistology. Results Pin1 protein level decreased in human atherosclerotic tissues and VSMCs, synchronously with increased VSMC senescence. Adenoviral‐mediated Pin1 overexpression rescued cellular senescence in atherosclerotic VSMCs, with concurrent down‐regulation of P53, p21, growth arrest and DNA‐damage‐inducible protein 45‐alpha (Gadd45a), phosphorylated retinoblastoma (p‐pRb), p65 and upregulation of cyclin subfamilies (cyclin B, D, and E), and cyclin‐dependent kinase subfamilies (2, 4, and 6), whereas Pin1 knockdown resulted in the converse effects, indicating that VSMC senescence mediated by Pin1 is an integrated response to diverse signals. In vivo data from ApoE−/− mice showed that treatment of juglone led to accelerated atherosclerosis development. Conclusions Altogether this work supports a role for Pin1 as a vital modulator of VSMC senescence, thereby providing a novel target for regulation and control of atherosclerosis. Clinical Relevance We found that decreased Pin1 protein level in human atherosclerotic tissues and vascular smooth muscle cells (VSMCs) was related to increased VSMC senescence, and in vivo data from apolipoprotein E−/−mice showed that treatment of a Pin1 inhibitor led to accelerated atherosclerosis development. This research indicated that interventions targeted at Pin1, such as cell‐specific drugs, are potential novel approaches to the retardation of atherosclerosis, in which VSMC senescence has a prominent role. Patients with atherosclerosis may benefit from pharmacologic interference with Pin1.

Thrombospondin-4 ablation reduces macrophage recruitment in adipose tissue and neointima and suppresses injury-induced restenosis in mice.

OBJECTIVE Thrombospondin-4 (Thbs4) is a member of the extracellular calcium-binding protein family and is linked to cell adhesion and migration. Given the involvement of Thbs4 in vascular inflammation, we hypothesized that Thbs4 plays a role in restenosis. METHODS AND RESULTS Here we show evidence that Thbs4 is upregulated in wire-injured mouse arteries and correlated with CD68 expression. Macrophage infiltration is reduced in both adipose tissue (AT) and neointima of Thbs4/ApoE double knockout (DKO) mice after injury. Moreover, Thbs4 deficiency prevents restenosis in ApoE KO mice fed a Western-type diet (WTD). Lethally irradiated DKO mice that receive bone marrow from ApoE KO or DKO mice have reduced neointima development. While considering related mechanisms, we note decreased chemokine production in both AT and neointima of DKO mice. In addition, vascular smooth muscle cells (VSMCs) derived from DKO mice display suppressed proliferation and migration in comparison with controls. Thioglycollate (TG)-induced macrophages from DKO mice show retarded adhesion to VSMCs. Recombinant Thbs4 promoted macrophage adhesion to VSMCs, and enhanced VSMC proliferation and migration. CONCLUSION Collectively, these data highlight the significance of Thbs4 in regulating macrophage accumulation and treating restenosis.

Features analysis of lower extremity arterial lesions in 162 diabetes patients.

Objective. This study aimed to investigate the angiographic manifestations of lower extremity atherosclerotic steno-occlusive disease in patients with diabetes. Materials and Methods. A total of 162 patients with diabetes were enrolled in this study. The angiographic findings of lower extremity arterial lesions were evaluated according to location (iliac, femoral, popliteal, and crural artery), type (stenosis or occlusion), and length (<5 cm, 5–10 cm, and >5 cm). Results. A total of 131 of 162 (80.9%) diabetics showed multiple segmental lesions, and 19.1% (31/162) presented single segmental lesions in the lower extremity artery. Crural artery was the mainly involved location (39/162, 85.8%). Among the recorded 660 lesions of 162 cases, 437 (66.2%) were occlusion lesions, while 223 (33.8%) were stenosis lesions. Of 437 occlusion lesions, 308 lesions (70.5%) were in crural artery. More than 10 cm occlusion lesion (242/392, 61.7%) was the main manifestation in crural artery, especially in anterior (92/127, 67.2%) and posterior tibial arteries (91/124, 73.4%), which was higher than that in iliac artery (8/33, 24.2%), popliteal artery (53/157, 33.8%), and femoral artery (11/78, 14.1%). Conclusion. In diabetic subjects with lower limb artery ischemia, the vascular involvement is extremely diffuse and particularly severe in crural arteries, with high prevalence of more than 10 cm occlusion lesions.

MiR-3202 – Promoted H5V Cell Apoptosis by Directly Targeting Fas Apoptotic Inhibitory Molecule 2 (FAIM2) in High Glucose Condition

Background Vascular complications are a major concern for patients with diabetes. Endothelial cells (ECs) play a key role in vascular function. MicroRNAs (miRNAs) have been shown to play an important role in mediating EC function; miRNAs are vulnerable to hyperglycemic conditions. Previous reports verified that Fas apoptotic inhibitory molecule 2 (FAIM2) can inhibit cell apoptosis through repressing the FAS-associated death domain protein (FADD) pathway. This current study was designed to explore the potential involvement of miR-3202 in the pathogenesis of ECs in high-glucose conditions. Material/Methods The aim of this study was to investigate the role of miR-3202 in regulating hyperglycemia-induced ECs by targeting FAIM2. The endothelial cell line H5V was cultured in a high-glucose condition to induce damage to FAIM2 expression in ECs; mimic and inhibition of miR-3202 were used to enhance and depress miR-3202’s function to explore its function on FAIM2. Results Our study showed that FAIM2 was inhibited by high-glucose conditions, and miRNA-3202 was induced by high-glucose conditions. FAIM2 was identified as the target gene of miRNA-3202; luciferase reporter assays confirmed that FAIM2 was downregulated by miR-3202 directly, that is, miR-3202 can upregulate Fas/FADD through inhibiting FAIM2. Conclusions MiR-3202 can promote EC apoptosis in hyperglycemic conditions, which demonstrated that EC apoptosis induced by high-glucose conditions partly depends on miR-3202 targeting FAIM2.

Quantification of Adventitial Vasa Vasorum Vascularization in Double-injury Restenotic Arteries

Background: Accumulating evidence indicates a potential role of adventitial vasa vasorum (VV) dysfunction in the pathophysiology of restenosis. However, characterization of VV vascularization in restenotic arteries with primary lesions is still missing. In this study, we quantitatively evaluated the response of adventitial VV to vascular injury resulting from balloon angioplasty in diseased arteries. Methods: Primary atherosclerotic-like lesions were induced by the placement of an absorbable thread surrounding the carotid artery of New Zealand rabbits. Four weeks following double-injury induced that was induced by secondary balloon dilation, three-dimensional patterns of adventitial VV were reconstructed; the number, density, and endothelial surface of VV were quantified using micro-computed tomography. Histology and immunohistochemistry were performed in order to examine the development of intimal hyperplasia. Results: Results from our study suggest that double injured arteries have a greater number of VV, increased luminal surface, and an elevation in the intima/media ratio (I/M), along with an accumulation of macrophages and smooth muscle cells in the intima, as compared to sham or single injury arteries. I/M and the number of VV were positively correlated (R 2 = 0.82, P < 0.001). Conclusions: Extensive adventitial VV neovascularization occurs in injured arteries after balloon angioplasty, which is associated with intimal hyperplasia. Quantitative assessment of adventitial VV response may provide insight into the basic biological process of postangioplasty restenosis.

Exosome-Based Translational Nanomedicine: The Therapeutic Potential for Drug Delivery

Recent reports have shown that exosomes are specialized membranous nanosized vesicles released by many cell types that have different biological effects and targeting specificities. Evidence shows that exosomes function as a delivery vehicle contributing to the therapeutic effects. However, most of the iceberg is under the water. In fact, different types of exosomes can be combined with specific drugs and serve as nanovectors so that personalized medicine needs are met. Exosomes are believed to have no cytotoxicity according to some research results. Currently, on the perceived advantages of exosomes, they are considered to be a next generation drug delivery system with high drug carrying capacity. This review summarizes some of these findings and highlights the potential of exosomes as carriers for therapeutic use.