Improving biological functions of endothelial progenitor cells (EPCs) is beneficial to maintaining endothelium homeostasis and promoting vascular re-endothelialization. Because macroautophagy/ autophagy has been documented as a double-edged sword in cell functions, its effects on EPCs remain to be elucidated. This study was designed to explore the role and molecular mechanisms of store-operated calcium entry (SOCE)-activated autophagy in proliferation of EPCs under hypercholesterolemia. We employed oxidized low-density lipoprotein (ox-LDL) to mimic hypercholesterolemia in bone marrowderived EPCs from rat. Ox-LDL dose-dependently activated autophagy flux, while inhibiting EPC proliferation. Importantly, inhibition of autophagy either by silencing Atg7 or by 3-methyladenine treatment, further aggravated proliferative inhibition by ox-LDL, suggesting the protective effects of autophagy against ox-LDL. Interestingly, ox-LDL increased STIM1 expression and intracellular Ca 2C concentration. Either Ca 2C chelators or deficiency in STIM1 attenuated ox-LDL-induced autophagy activation, confirming the involvement of SOCE in the process. Furthermore, CAMKK2 (calcium/ calmodulin-dependent protein kinase kinase 2, b) activation and MTOR (mechanistic target of rapamycin [serine/threonine kinase]) deactivation were associated with autophagy modulation. Together, our results reveal a novel signaling pathway of SOCE-CAMKK2 in the regulation of autophagy and offer new insights into the important roles of autophagy in maintaining proliferation and promoting the survival capability of EPCs. This may be beneficial to improving EPC transplantation efficacy and enhancing vascular reendothelialization in patients with hypercholesterolemia.
The dysfunction of endothelial progenitor cells (EPCs) has been shown to prevent endothelial repair during the development of atherosclerosis (AS). Previous studies have revealed that store-operated calcium entry (SOCE) is an important factor in regulating EPC functions. However, whether this is also the mechanism in AS has not been elucidated. Therefore, we evaluated the role of SOCE in EPCs isolated from an atherosclerotic mouse model. Atheromatous plaques were more frequent in the aortas of ApoE -/ -mice fed a high-fat diet for 16 weeks compared with controls, and the proliferative and migratory activities of atherosclerotic EPCs were significantly decreased. Accordingly, SOCE amplitude, as well as spontaneous or VEGF-induced Ca 2 + oscillations, decreased in atherosclerotic EPCs. These results may be associated with the downregulated expression of Stim1, Orai1, and TRPC1, which are major mediators of SOCE. In addition, eNOS expression and phosphorylation at Ser 1177 , which are critical regulators of EPC function, were markedly reduced in the atherosclerotic EPCs. The impairment of eNOS activity could also be induced by using an SOCE inhibitor or by Stim1 gene silencing, indicating a link between the activities of eNOS and SOCE in AS. Furthermore, decreased SOCE function inhibited EPC proliferation and migration in vitro. In conclusion, our results showed that the reduction of SOCE induced EPC dysfunction during AS, potentially through downregulation of store-operated calcium channel (SOCC) components and impaired eNOS activity. Approaches aimed at reestablishing SOCE activity may thus improve the function of EPCs during AS.
The purpose of this article was to use finite element analysis (FEA) to study the relationship of tibial tunnel (TT) with fracture pattern and implants. A computed tomography scan of full-length tibia and fibula was obtained. Models were built after three-dimensional reconstruction. The corresponding plates and screws were constructed and assembled together with fracture models. FEA was performed and contourplots were output. The Von Mises stresses of nodes and displacements of elements were extracted. Student’s t test was used to compare the values of Von Mises stresses and displacements between corresponding models. Differences in Von Mises stresses and displacements of fragments and implants between models with and without TT were nearly all statistically significant. However, the displacements of fragments and implants for all models were < 2 mm. TT in fracture models had larger Von Mises stresses than TT in intact tibial model. However, displacements of TT in fracture models showed similar or even smaller results to those in intact tibial model. Although almost all the tested parameters were statistically significant, differences were small and values were all below the clinical threshold. This study could promote open reduction and internal fixation with one-stage reconstruction for treatment of tibial plateau fractures associated with anterior cruciate ligament (ACL) ruptures.
Aims: To evaluate the feasibility of assessing regional myocardial perfusion using real-time myocardial contrast echocardiography (MCE) at rest for detecting coronary microcirculation abnormalities in methamphetamine abusers.Material and methods: Twenty-two male methamphetamine abusers (11 without chest pain, 11 with chest pain), free of ascertained coronary artery disease, were enrolled in this study. A control group of 22 age-matched male healthy participants was studied for comparison. Standard 2D, flow and tissue Doppler echo with measurements of cardiac morphologic and functional indicators,MCE with measurements of regional myocardial perfusion were performed, respectively.Results: Compared to healthy participants, methamphetamine abusers had higher blood pressure, greater left ventricular mass index and more impaired diastolic function, with preserved cardiac sizes and systolic function. Methamphetamine abusers with chest pain had a faster heart rate than those without chest pain and healthy participants. MCE in methamphetamine abusers, especially with chest pain, had significant longer contrast agent arrival times, less functional capillary blood volumes, slower microvascular flow velocities and less myocardial perfusion than healthy participants (p<0.05). Moreover, along with the increases of dosage and duration of use (from group A to group C, group A: 1-2 g/day, <2 years; group B: 2-3 g/day, 2-5 years; group C: >3 g/day, >5 years) the reductions in the myocardial perfusion indices were more significant (p<0.01). The cutoff value with 5.1 dB2/s of the myocardial perfusion at the left ventricular apex had a sensitivity of 87.5%, specificity of 75.2% and accuracy of 81.9% for differentiating methamphetamine abusers from normal subjects.Conclusions: Real-time MCE can effectively detect coronary microcirculation abnormalities in methamphetamine abusers at rest and myocardial perfusion is significantly reduced in methamphetamine abusers. This finding may be involved in the occurrence and development of cardiac damage.
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