Exosomes Secreted During Myogenic Differentiation of Human Fetal Cartilage-Derived Progenitor Cells Promote Skeletal Muscle Regeneration through miR-145-5p

BACKGROUND@#Currently, there is no apparent treatment for sarcopenia, which is characterized by diminished myoblast function. We aimed to manufacture exosomes that retain the myogenic differentiation capacity of human fetal cartilagederived progenitor cells (hFCPCs) and investigate their muscle regenerative efficacy in myoblasts and a sarcopenia rat model. @*METHODS@#The muscle regeneration potential of exosomes (F-Exo) secreted during myogenic differentiation of hFCPCs was compared to human bone marrow mesenchymal stem cells-derived (hBMSCs) exosomes (B-Exo) in myoblasts and sarcopenia rat model. The effect of F-Exo was analyzed through known microRNAs (miRNAs) analysis. The mechanism of action of F-Exo was confirmed by measuring the expression of proteins involved in the Wnt signaling pathway. @*RESULTS@#F-Exo and B-Exo showed similar exosome characteristics. However, F-Exo induced the expression of muscle markers (MyoD, MyoG, and MyHC) and myotube formation in myoblasts more effectively than B-Exo. Moreover, F-Exo induced greater increases in muscle fiber cross-sectional area and muscle mass compared to B-Exo in a sarcopenia rat. The miR-145-5p, relevant to muscle regeneration, was found in high concentrations in the F-Exo, and RNase pretreatment reduced the efficacy of exosomes. The effects of F-Exo on the expression of myogenic markers in myoblasts were paralleled by the miR-145-5p mimics, while the inhibitor partially negated this effect. F-Exo was involved in the Wnt signaling pathway by enhancing the expression of Wnt5a and b-catenin. @*CONCLUSION@#F-Exo improved muscle regeneration by activating the Wnt signaling pathway via abundant miR-145-5p, mimicking the remarkable myogenic differentiation potential of hFCPCs.

Exosomes from IL-1b-Primed Mesenchymal Stem Cells Inhibited IL-1b- and TNF-a-Mediated Inflammatory Responses in Osteoarthritic SW982 Cells

BACKGROUND@#Exosomes from mesenchymal stem cells (MSCs) show anti-inflammatory effect on osteoarthritis (OA); however, their biological effect and mechanism are not yet clearly understood. This study investigated the anti-inflammatory effect and mechanism of MSC-derived exosomes (MSC-Exo) primed with IL-1β in osteoarthritic SW982 cells. @*METHODS@#SW982 cells were treated with interleukin (IL)-1β and tumor necrosis factor (TNF)-α to induce the OA phenotype. The effect of exosomes without priming (MSC-Exo) or with IL-1β priming (MSC-IL-Exo) was examined on the expression of pro- or anti-inflammatory factors, and the amount of IκBα was examined in SW982 cells. Exosomes were treated with RNase to remove RNA. The role of miR-147b was examined using a mimic and an inhibitor. @*RESULTS@#MSC-IL-Exo showed stronger inhibitory effects on the expression of pro-inflammatory cytokines (IL-1β, IL-6, and monocyte chemoattractant protein-1) than MSC-Exo. The expression of anti-inflammatory factors (SOCS3 and SOCS6) was enhanced by MSCs-IL-Exo. Priming with IL-1β increased RNA content in MSC-IL-Exo, and pretreatment with RNase abolished anti-inflammatory effect in SW982 cells. miR-147b was found in much larger amounts in MSC-IL-Exo than in MSC-Exo. The miR-147b mimic significantly inhibited the expression of inflammatory cytokines, while the miR-147b inhibitor only partially blocked the anti-inflammatory effect of MSC-IL-Exo. MSC-IL-Exo and miR-147b mimic inhibited the reduction of IκBα, an nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibitor, by IL-1β and TNF-α. @*CONCLUSION@#This study showed that MSC exosomes with IL-1β priming exhibit significantly enhanced anti-inflammatory activity in osteoarthritic SW982 cells. The effect of IL-1β-primed MSC exosomes is mediated by miRNAs such as miR-147b and involves inhibition of the NF-κB pathway.

Exosomes from IL-1b-Primed Mesenchymal Stem Cells Inhibited IL-1b- and TNF-a-Mediated Inflammatory Responses in Osteoarthritic SW982 Cells

BACKGROUND@#Exosomes from mesenchymal stem cells (MSCs) show anti-inflammatory effect on osteoarthritis (OA); however, their biological effect and mechanism are not yet clearly understood. This study investigated the anti-inflammatory effect and mechanism of MSC-derived exosomes (MSC-Exo) primed with IL-1β in osteoarthritic SW982 cells. @*METHODS@#SW982 cells were treated with interleukin (IL)-1β and tumor necrosis factor (TNF)-α to induce the OA phenotype. The effect of exosomes without priming (MSC-Exo) or with IL-1β priming (MSC-IL-Exo) was examined on the expression of pro- or anti-inflammatory factors, and the amount of IκBα was examined in SW982 cells. Exosomes were treated with RNase to remove RNA. The role of miR-147b was examined using a mimic and an inhibitor. @*RESULTS@#MSC-IL-Exo showed stronger inhibitory effects on the expression of pro-inflammatory cytokines (IL-1β, IL-6, and monocyte chemoattractant protein-1) than MSC-Exo. The expression of anti-inflammatory factors (SOCS3 and SOCS6) was enhanced by MSCs-IL-Exo. Priming with IL-1β increased RNA content in MSC-IL-Exo, and pretreatment with RNase abolished anti-inflammatory effect in SW982 cells. miR-147b was found in much larger amounts in MSC-IL-Exo than in MSC-Exo. The miR-147b mimic significantly inhibited the expression of inflammatory cytokines, while the miR-147b inhibitor only partially blocked the anti-inflammatory effect of MSC-IL-Exo. MSC-IL-Exo and miR-147b mimic inhibited the reduction of IκBα, an nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibitor, by IL-1β and TNF-α. @*CONCLUSION@#This study showed that MSC exosomes with IL-1β priming exhibit significantly enhanced anti-inflammatory activity in osteoarthritic SW982 cells. The effect of IL-1β-primed MSC exosomes is mediated by miRNAs such as miR-147b and involves inhibition of the NF-κB pathway.

Association between the Red Cell Distribution Width and Vasospastic Angina in Korean Patients

PURPOSE: The association between the red cell distribution width (RDW) and vasospastic angina (VSA) has not been elucidated. We investigated the association of the RDW with the incidence and angiographic subtypes of VSA in Korean patients. MATERIALS AND METHODS: A total of 460 patients who underwent intracoronary ergonovine provocation tests were consecutively enrolled and classified into two groups: the VSA group (n=147, 32.0%) and non-VSA group (n=313, 68.0%). The subjects were classified into 3 subgroups (tertiles) according to the baseline level of RDW assessed before the angiographic provocation test. RESULTS: The VSA group had a higher RDW than the non-VSA group (12.9±0.8% vs. 12.5±0.7%, p=0.013). The high RDW level demonstrated an independent association with the high incidence of VSA [second tertile: hazard ratio (HR) 1.96 (1.13-2.83), third tertile: HR 2.33 (1.22-3.47), all p<0.001]. Moreover, the highest RDW tertile level had a significant association with the prevalence of the mixed-type coronary spasm [HR 1.29 (1.03-1.59), p=0.037]. CONCLUSION: The high level of RDW was significantly associated with the prevalence of VSA and the high-risk angiographic subtype of coronary spasm, suggesting that a proactive clinical investigation for VSA could be valuable in Korean patients with an elevated RDW.

Microalbuminuria is Independently Associated with Arterial Stiffness and Vascular Inflammation but not with Carotid Intima-Media Thickness in Patients with Newly Diagnosed Type 2 Diabetes or Essential Hypertension

The association between microalbuminuria (MAU) and the indices of macrovascular complication in patients with newly diagnosed type 2 diabetes (D) or essential hypertension (H) was evaluated. Total 446 patients were classified into four groups according to the urinary albumin-to-creatinine ratio: MAU-D (n = 104), normoalbuminuria (NAU)-D (n = 114), MAU-H (n = 116), and NAU-H (n = 112). The indices of macrovascular complication including arterial stiffness evaluated by pulse-wave-velocity (PWV), carotid intima-media thickness (IMT), and vascular inflammation marked by high-sensitivity C-reactive protein (hsCRP) were assessed. PWV, IMT, and hsCRP were higher in patients with MAU than in those with NAU in both diabetes and hypertension groups. In both MAU-D and MAU-H groups, PWV and hsCRP levels were positively correlated with MAU level (MAU-D: r = 0.47, 0.41, MAU-H: r = 0.36, 0.62, respectively, P < 0.05). Additionally, PWV and hsCRP were independent factors predicting MAU (diabetes group: OR 1.85, 1.54, hypertension group: OR 1.38, 1.51, respectively, P < 0.001), but not IMT. MAU is independently associated with arterial stiffness and vascular inflammation but not with IMT in patients with newly diagnosed type 2 diabetes or essential hypertension, which emphasizes the importance of proactive clinical investigations for atherosclerotic complications in patients with MAU, even in newly diagnosed diabetes or hypertension.

The Effect of Cilostazol on Stent Thrombosis After Drug-Eluting Stent Implantation

BACKGROUND AND OBJECTIVES: Placement of drug-eluting stents (DES) can be complicated by stent thrombosis; prophylactic antiplatelet therapy has been used to prevent such events. We evaluated the efficacy of cilostazol with regard to stent thrombosis as adjunctive antiplatelet therapy. SUBJECTS AND METHODS: A total of 1,315 patients (846 males, 469 females) were prospectively enrolled and analyzed for the frequency of stent thrombosis. Patients with known risk factors for stent thrombosis, except diabetes and acute coronary syndrome, were excluded from the study. All patients maintained antiplatelet therapy for at least six months. To evaluate the effects of cilostazol as another option for antiplatelet therapy, triple antiplatelet therapy (aspirin+clopidogrel+cilostazol, n=502) was compared to dual antiplatelet therapy (aspirin+clopidogrel, n=813). Six months after stent placement, all patients received only two antiplatelet drugs: treatment either with cilostazol+aspirin (cilostazol group) or clopidogrel+aspirin (clopidogrel group). There were 1,033 patients (396 in cilostazol group and 637 in clopidogrel group) that maintained antiplatelet therapy for at least 12 months and were included in this study. Stent thrombosis was defined and classified according to the definition reported by the Academic Research Consortium (ARC). RESULTS: defined and classified according to the definition reported by the Academic Research Consortium (ARC). RESULTS: During follow-up (561.7+/-251.4 days), 15 patients (1.14%) developed stent thrombosis between day 1 to day 657. Stent thrombosis occurred in seven patients (1.39%) on triple antiplatelet therapy and four patients (0.49%) on dual antiplatelet therapy (p=NS) within the first six months after stenting. Six months and later, after stent implantation, one patient (0.25%) developed stent thrombosis in the cilostazol group, and three (0.47%) in the clopidogrel group (p=NS). CONCLUSION: During the first six months after DES triple antiplatelet therapy may be more effective than dual antiplatelet therapy for the prevention of stent thrombosis. However, after the first six months, dual antiplatelet treatment, with aspirin and cilostazol, may have a better cost benefit ratio for the prevention of stent thrombosis.

Significance of Inflammatory Markers in Diabetic Patients with Stable Coronary Artery Disease

BACKGROUND/AIMS: Patients with diabetes are prone to coronary artery disease (CAD); however, the majority of diabetic patients show normal coronary arteries. We examined differences in the clinical aspects of diabetic patients with insignificant and with significant stenosis of the coronary artery. METHODS: A total of 418 consecutive diabetic patients with stable angina who had undergone coronary angiography from January 2004 to March 2007 were included in this study. Patients were subdivided into control and CAD groups and then clinical characteristics and CAD-associated factors were evaluated. RESULTS: A total of 92 (22%) patients were assigned to the control group and 326 (78%) patients were assigned to the CAD group. Using univariate regression analysis, we found that patients with CAD were significantly older (control vs. CAD; 59+/-21 vs. 64.7+/-33.7, years, p<0.001), had a longer duration of diabetes (8.2+/-21.8 vs. 10.2+/-29.8, years, p=0.027), higher titers of high sensitivity C-reactive protein (hsCRP; 0.3+/-6.79 vs. 0.9+/-12.6, mg/dL, p=0.015), and increased hemoglobin A1c (HbA1c) levels (7.1+/-3.8 vs. 7.5+/-4.8, %, p=0.007) compared to control patients. Multivariate regression analysis showed that only differences in age, hsCRP, and HbA1c were statistically significant. When patients were subdivided into groups based on hsCRP levels (208 patients in the low group [49.8%], 210 patients in the high group [50.2%]), we found that patients with higher hsCRP levels showed more frequent multivessel disease. CONCLUSIONS: In diabetic patients, age, hsCRP, and HbA1c were associated with stable CAD. Among these factors, hsCRP levels were significantly correlated with multivessel involvement in diabetic CAD. Therefore, high hsCRP levels may be a strong predictor for atherosclerotic progression of the coronary arteries in diabetic patients, suggesting that regular screening tests should be performed.

Erratum: The usefulness of ischemia modified albumin as an early ischemic marker to detect coronary artery disease in patients with chest pain presenting to the emergency department / 대한내과학회지

No abstract available.

Utilization Pattern of Drug-Eluting Stents and Prognosis of Patients Who Underwent Drug-Eluting Stenting Compared with Bare Metal Stenting in the Real World

BACKGROUND AND OBJECTIVES: Currently, the drug-eluting stent (DES) has been widely used because of its excellent clinical outcome. We compared the utilization patterns and clinical outcomes between the DES and the bare metal stent (BMS) in the real world. SUBJECTS AND METHODS: We retrospectively reviewed the stent registry at the Catholic Medical Center between January 2002 and October 2004. There were 1120 patients treated with DES (n=1837) who were compared to 910 patients who received BMS implantation (n=1238). RESULTS: Patients with de novo lesions in the DES group more frequently had multivessel disease and received a greater number of stents than those in BMS group (p<0.001). The mean diameter of inserted stents was smaller in the DES group (p<0.001). The follow-up rate for clinical and angiographic evaluations at 6 months after stenting was 91% and 65% (n=592) in the BMS group and 90% and 74% (n=829) in the DES group, respectively. The rate of major adverse cardiac events (death, nonfatal myocardial infarction, or target vessel revascularization) at 6 months was 7.3% in the DES group and 17.5% in the BMS group (p<0.001). The rates of target vessel revascularization in the DES group and in the BMS group were 4.2% and 12.9%, respectively (p<0.001). CONCLUSION: The patients in the DES group had longer length, smaller diameter and higher number of placed stents, compared to the BMS group. The rates of revascularization and major adverse cardiac events in the DES group were lower than those in the BMS group.

Comparison of the Long-Term Prognosis between Coronary Vasospasm and Intermediate Vasoconstriction Induced by the Administration of Acetylcholine

BACKGROUND AND OBJECTIVES: The degree of coronary vasoconstriction induced by acetylcholine administeration can vary. We compared the prognosis between coronary vasospasm and intermediate vasoconstriction, which were both induced by acetylcholine administration. SUBJECTS AND METHODS: The subjects were 156 patients with the coronary vasospasm or intermediate vasoconstriction, as observed on the acetylcholine provocation tests that were performed from January, 2000 to January, 2004. The patients with a spasm showing greater than 90% reduction of vessel diameter along with chest pain or ST changes or both were classified as having 'strong positive vasospasm' (n=113). The patients with 70-90% reduction of diameter were classified as having 'intermediate vasoconstriction' (n=43). The mortality, frequency of chest pain and clinical events were then analyzed. RESULTS: A smoking history (p<0.001) and multivessel involvement (p=0.02) were more frequent in the strong positive group. We compared the mortality and clinical events due to chest pain during the average 26.4+/-14.1 months of follow-up. There were 5 patients (4.4%) who incurred cardiac death in the strong positive group as compared with none in the intermediate group. The total clinical events were more frequent in the strong positive group (p<0.001). Also, the strong positive group showed a significantly higher frequency of chest pain (p<0.001). CONCLUSION: The long-term prognosis of the intermediate vasoconstriction was better than that of strong positive vasospasm. Thus, the intermediate vasoconstriction must be ruled out by strict application of the positive criteria for the acetylcholine provocation test.