ANGPTL2 aggravates LPS-induced septic cardiomyopathy via NLRP3-mediated inflammasome in a DUSP1-dependent pathway.

Angiopoietin-like protein 2 (ANGPTL2) was implicated in various cardiovascular diseases; however, its role in lipopolysaccharide (LPS)-related septic cardiomyopathy remains unclear. Herein, mice were exposed to LPS to generate septic cardiomyopathy, and adeno-associated viral vector was employed to overexpress ANGPTL2 in the myocardium. Besides, mice were treated with adenoviral vector to knock down ANGPTL2 in hearts. ANGPTL2 expressions in hearts and cardiomyocytes were upregulated by LPS challenge. ANGPTL2 overexpression aggravated, while ANGPTL2 silence ameliorated LPS-associated cardiac impairment and inflammation. Mechanically, we found that ANGPTL2 activated NLRP3 inflammasome via suppressing DUSP1 signaling, and NLRP3 knockdown abrogated the detrimental role of ANGPTL2 in aggravating LPS-induced cardiac inflammation. Furthermore, DUSP1 overexpression significantly inhibited ANGPTL2-mediated NLRP3 activation, and subsequently improved LPS-related cardiac dysfunction. In summary, ANGPTL2 exacerbated septic cardiomyopathy via activating NLRP3-mediated inflammation in a DUSP1-dependent manner, and our study uncovered a promising therapeutic target in preventing septic cardiomyopathy.

Four-corners traction combined with continuous everting suture technique as a modification in bicaval anastomosis for orthotopic heart transplantation.

BACKGROUND: Although standard bicaval techniques has become popular in orthotopic heart transplantation, distortion, bleeding, thrombosis and arrhythmia were still causes for concern. This study was designed to compare the standard bicaval techniques and modified bicaval techniques in our institution. MATERIALS AND METHODS: A total of 70 recipients underwent orthotopic heart transplantation at our center from June 2015 to April 2019 (standard group = 24 cases, modified group = 46 cases). The average follow-up period was 46.4 ± 17.4 months. Atrioventricular cavity diameter was measured by ultrasonography and left atrial morphology was evaluated by CT-angiography and three-dimensional reconstruction. RESULTS: Recipients in both groups were similar with pre-operative characteristics. Total ischemic, cardiopulmonary bypass and cross-clamp times were similar. The modified bicaval techniques group has a significantly fewer blood transfusion, lower post-transplant tricuspid regurgitation grade and the incidence of post-operative atrial arrhythmia than standard bicaval techniques group. CT-angiography and three-dimensional reconstruction illustrated ideal and physiologic left atrial morphological structure. Short-term survival differed significantly and the cumulative proportion of survival was significantly higher in the modified bicaval techniques group than that in the standard bicaval techniques group. CONCLUSIONS: This study showed that modified bicaval techniques offers a better early outcome than standard bicaval techniques. The significant reduction of intraoperative blood transfusion and post-transplant tricuspid regurgitation grade in the modified bicaval techniques group may has a major impact on the short-term survival.

Effect of novel bicaval anastomosis technique for transplantation with and without prior cardiac surgery history.

BACKGROUND: To evaluate the graft outcomes after orthotopic heart transplantation (HTx) with a novel bicaval anastomosis technique between recipients with and without a history of prior cardiac surgery. METHODS: Of 70 patients who underwent HTx with a novel four-corners traction bicaval anastomosis technique from August 2017 to November 2019, 60 recipients underwent the HTx procedure as their first cardiac surgery (group A), while 10 recipients underwent HTx after prior cardiac surgery (group B). Patients in the two groups were compared in terms of their preoperative baseline variables such as etiological categories, history of blood transfusion and panel reactive antibody (PRA), intraoperative operation time and blood infusion volume, postoperative treatment time, and complications such as acute rejection and 30-day mortality as well as survival rates. RESULTS: Preoperative variables were comparable in group A and group B except for the history of blood transfusion (0% vs. 90.0%, P<0.001, respectively); the level of PRA was 7.5%±5.8% and 9.5%±10.9% for group A and B, respectively (P=0.583), but the time of the operation was nearly 1 hour longer for group B than group A (all P<0.05). No cases of left atrial thrombosis and donor heart distortion were observed in either group. Reoperation (1.7% vs. 10.0%, P=0.267), infection (0% vs. 10.0%, P=0.142), other postoperative complications as well as the 30-day mortality (1.7% vs. 10.0%, P=0.267), and postoperative survival rates (91.5% vs. 90.0%, P=0.805) were comparable between the two groups (all P>0.05). CONCLUSIONS: Four-corner traction bicaval anastomosis combined with a continuous everting suture technique may result in approximately comparable prognoses for heart recipients with a history of cardiac surgery when compared with those without a history of cardiac surgery and this technique may reduce the incidence of left atrial thrombosis and distortion. Further follow-up of the long-term outcomes will be required to validate these results.

Exosomes from dendritic cells with Mettl3 gene knockdown prevent immune rejection in a mouse cardiac allograft model.

We have previously demonstrated that Mettl3-silencing dendritic cells (DCs) exhibited immature properties and prolonged allograft survival in a murine heart transplantation model. Exosomes derived from donor DCs (Dex) are involved in the immune rejection of organ transplantation, and blocking Dex transfer may suppress immune rejection. Herein, this study aimed to investigate whether Mettl3 knockdown inhibits the secretion and activity of donor Dex, thereby inhibiting donor Dex-mediated immune rejection. The imDex, mDex, shCtrl-mDex, and shMettl3-mDex were obtained from the culture supernatant of DCs (immature DCs, mature DCs, shCtrl-infected mature DCs, shMettl3-infected mature DCs) derived from donor BALB/c mouse bone marrow and then co-cultured with splenic T cell lymphocyte suspension from recipient C57BL/6 mice in vitro or injected into recipient C57BL/6 mice before the cardiac transplantation. Donor shMettl3-mDex expressed lower concentration of exosomes and lower expression of Mettl3, Dex markers (ICAM-1, MHC-I, MHC-II), as well as lower ability to activate T cell immune response than shCtrl-mDex. Administration of donor shMettl3-mDex attenuated immune rejection after mouse heart transplantation and prolonged the allograft survival. In summary, Mettl3 knockdown inhibits the immune rejection of Dex in a mouse cardiac allograft model.

Light-Dark Modulates Root Hydrotropism Associated with Gravitropism by Involving Amyloplast Response in Arabidopsis.

The role of amyloplasts in the interactions between hydrotropism and gravitropism has been previously described. However, the effect of light-dark on the interactions between the two tropisms remains unclear. Here, by developing a method that makes it possible to mimic natural conditions more closely than the conventional lab conditions, we show that hydrotropism is higher in wild-type Arabidopsis seedlings whose shoots are illuminated but whose roots are grown in the dark compared with seedlings that are fully exposed to light. Root gravitropism is substantially decreased because of the reduction of amyloplast content in the root tip with decreased gene expression in PGM1 (a key starch biosynthesis gene), which may contribute to enhanced root hydrotropism under darkness. Furthermore, the starch-deficient mutant pgm1-1 exhibits greater hydrotropism compared with wild-type. Our results suggest that amyloplast response and starch reduction occur under light-dark modulation, followed by decreased gravitropism and enhanced hydrotropism in Arabidopsis root.

Comparative analysis reveals gravity is involved in the MIZ1-regulated root hydrotropism.

Hydrotropism is the directed growth of roots toward the water found in the soil. However, mechanisms governing interactions between hydrotropism and gravitropism remain largely unclear. In this study, we found that an air system and an agar-sorbitol system induced only oblique water-potential gradients; an agar-glycerol system induced only vertical water-potential gradients; and a sand system established both oblique and vertical water-potential gradients. We employed obliquely oriented and vertically oriented experimental systems to study hydrotropism in Arabidopsis and tomato plants. Comparative analyses using different hydrotropic systems showed that gravity hindered the ability of roots to search for obliquely oriented water, whilst facilitating roots' search for vertically oriented water. We found that the gravitropism-deficient mutant aux1 showed enhanced hydrotropism in the oblique orientation but impaired root elongation towards water in the vertical orientation. The miz1 mutant exhibited deficient hydrotropism in the oblique orientation but normal root elongation towards water in the vertical orientation. Importantly, in contrast to miz1, the miz1/aux1 double mutant exhibited hydrotropic bending in the oblique orientation and attenuated root elongation towards water in the vertical orientation. Our results suggest that gravitropism is required for MIZ1-regulated root hydrotropism in both the oblique orientation and the vertical orientation, providing further insight into the role of gravity in root hydrotropism.

Asiatic Acid Protects against Doxorubicin-Induced Cardiotoxicity in Mice.

The use of doxorubicin (DOX) can result in depression of cardiac function and refractory cardiomyopathy. Currently, there are no effective approaches to prevent DOX-related cardiac complications. Asiatic acid (AA) has been reported to provide cardioprotection against several cardiovascular diseases. However, whether AA could attenuate DOX-related cardiac injury remains unclear. DOX (15 mg/kg) was injected intraperitoneally into the mice to mimic acute cardiac injury, and the mice were given AA (10 mg/kg or 30 mg/kg) for 2 weeks for protection. The data in our study found that AA-treated mice exhibited attenuated cardiac injury and improved cardiac function in response to DOX injection. AA also suppressed myocardial oxidative damage and apoptosis without affecting cardiac inflammation in DOX-treated mice. AA also provided protection in DOX-challenged cardiomyocytes, improved cell viability, and suppressed intracellular reactive oxygen species (ROS) in vitro. Detection of signaling pathways showed that AA activated protein kinase B (AKT) signaling pathway in vivo and in vitro. Furthermore, we found that AA lost its protective effects in the heart with AKT inactivation. In conclusion, our results found that AA could attenuate DOX-induced myocardial oxidative stress and apoptosis via activation of the AKT signaling pathway.

Epidemiologic and clinical characteristics of heart transplant recipients during the 2019 coronavirus outbreak in Wuhan, China: A descriptive survey report.

BACKGROUND: The epidemiologic and clinical characteristics of heart transplant (HTx) recipients during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic remains unclear. We studied the characteristics of HTx recipients from December 20, 2019, to February 25, 2020, in an effort to understand their risk and outcomes. METHODS: All accessible HTx recipients were included in this single-center retrospective study. We collected information on the recipients using a web-based questionnaire as well as the hospital database. RESULTS: We followed 87 HTx recipients (72.4% were men, and the average age was 51 years). A total of 79 recipients resided in Hubei, and 57 recipients had a Wuhan-related history of travel or contact. Most took precautionary measures while in contact with suspicious crowds, and 96.6% of the families and communities undertook prevention and quarantine procedures. Four upper airway infections were reported, and 3 of them tested negative for SARS-CoV-2 (the fourth recovered and was not tested). All cases were mild and successfully recovered after proper treatment. Laboratory results of 47 HTx cases within the last 2 months were extracted. Of these, 21.3% of recipients had pre-existing lymphopenia, and 87.2% of recipients had a therapeutic concentration of tacrolimus (5-12 ng/ml). Liver and kidney insufficiency was seen in 5 and 6 recipients, respectively. CONCLUSION: HTx recipients who practiced appropriate prevention measures had a low rate of infection with SARS-CoV-2 and transition to the associated disease COVID-19. These early data will require confirmation as the pandemic establishes around the world.

Dendritic cells with METTL3 gene knockdown exhibit immature properties and prolong allograft survival.

Maturation of dendritic cells (DCs) initiates adaptive immune responses and thereby provokes allograft rejection. Here, this study aimed to explore the effect of Methyltransferase-like protein 3 (METTL3) silencing on DC function and the role of METTL3-silencing donor DCs in the immune response after mouse heart transplantation. Bone marrow-derived DCs from donor BALB/c mice were infected with lentiviruses expressing METTL3-specific short hairpin RNA (LV-METTL3 shRNA) to silence METTL3. Then METTL3-silencing DCs were treated with lipopolysaccharide (LPS) for another 48 h to induce DC maturation. Recipient C57BL/6 mice were injected with phosphate-buffered saline (PBS), immature DCs, and METTL3 shRNA-DCs prior to the cardiac transplantation involving the transfer of hearts from donor BALB/c mice to recipient C57BL/6 mice. In vitro we demonstrated that METTL3-silencing DCs had lower expression of MHCII, costimulatory molecules (CD80, CD86), and DC-related cytokines (IFN-γ, IL-12) as well as lower ability to activate T-cell proliferation, which were consistent with the characteristics of tolerogenic DCs. In vivo we found that METTL3-silencing donor DCs induced immune tolerance after mouse heart transplantation and prolonged the allograft survival, which might be associated with Th1/Th2 immune deviation. In summary, METTL3-silencing DCs exhibit immature properties and prolong allograft survival.

Avß3 Single-Stranded DNA Aptamer Attenuates Vascular Smooth Muscle Cell Proliferation and Migration via Ras-PI3K/MAPK Pathway.

OBJECTIVES: To observe the effect of avß3 single-stranded (ss) DNA on proliferation and migration of vascular smooth muscle cells (VSMCs) and its potential mechanism. BACKGROUND: Percutaneous transluminal coronary angioplasty (PTCA) is currently the preferred method for the treatment of coronary heart disease. However, vascular restenosis still occurs after PTCA treatment, severely affecting the clinical efficacy of PTCA. Integrin avß3 single-stranded (ss) DNA on proliferation and migration of vascular smooth muscle cells (VSMCs) and its potential mechanism. METHODS: In this experiment, we used systematic evolution of ligands by exponential enrichment (SELEX) to screen out avß3 single-stranded (ss) DNA on proliferation and migration of vascular smooth muscle cells (VSMCs) and its potential mechanism. ß3 single-stranded (ss) DNA on proliferation and migration of vascular smooth muscle cells (VSMCs) and its potential mechanism. ß3 single-stranded (ss) DNA on proliferation and migration of vascular smooth muscle cells (VSMCs) and its potential mechanism. ß3 single-stranded (ss) DNA on proliferation and migration of vascular smooth muscle cells (VSMCs) and its potential mechanism. RESULTS: In the present study, we found that avß3 single-stranded (ss) DNA on proliferation and migration of vascular smooth muscle cells (VSMCs) and its potential mechanism. P < 0.05). Avß3 single-stranded (ss) DNA on proliferation and migration of vascular smooth muscle cells (VSMCs) and its potential mechanism. P < 0.05). AvP < 0.05). Av. CONCLUSIONS: The findings suggest that avß3 ssDNA inhibited the proliferation and migration of VSMCs by suppressing the activation of Ras-PI3K/MAPK signaling.ß3 single-stranded (ss) DNA on proliferation and migration of vascular smooth muscle cells (VSMCs) and its potential mechanism.

Avß3 single-stranded DNA aptamer attenuates vascular restenosis via Ras-PI3K/MAPK pathway in rats after percutaneous transluminal coronary angioplasty.

Our aim was to investigate the effect of avß3 single-stranded DNA aptamer (avß3 ssDNA) on vascular restenosis in rats after percutaneous transluminal coronary angioplasty (PTCA) via the Ras-PI3K/MAPK pathway. Sixty Sprague-Dawley rats were randomly divided into six groups: sham-operated, PTCA, PTCA+cilengitide (18 mg/kg, n = 8), and avß3 ssDNA treatment at 50, 100, and 200 µg/kg. Hematoxylin-eosin staining was performed to evaluate the successful establishment of the PTCA model and to assess the degree of intimal hyperplasia. Immunofluorescence and in situ hybridization were carried out to observe the level of avß3. Immunohistochemistry was used to detect the expression of E-cadherin, N-cadherin, α-smooth muscle actin (α-SMA), angiotensin 1 (ANG1), and ANG2. The expression of osteopontin (OPN), focal adhesion kinase (FAK), Ras, mitogen-activated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), signal transducer and activator of transcription 1 (STAT1), and GTPase was observed by the western blot and quantitative reverse transcription polymerase chain reaction. Compared with rats subjected to PTCA only, those treated with avß3 ssDNA showed significantly decreased vascular occlusion rate (P < .05). The protein expression of avß3, OPN, p-FAK, ANG2, and E-cadherin was significantly increased by avß3 ssDNA (P < .05), while the levels of ANG1, α-SMA, N-cadherin Ras, MAPK, PI3K, STAT1, and GTPase were significantly decreased (P < .05). Avß3 ssDNA reduced the proliferation, migration, epithelial-mesenchymal transition, and vascular remodeling of vascular smooth muscle cells, and the mechanism may be related to the Ras-PI3K/MAPK pathway.

miR-200a Attenuated Doxorubicin-Induced Cardiotoxicity through Upregulation of Nrf2 in Mice.

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) was closely involved in doxorubicin- (DOX-) induced cardiotoxicity. MicroRNA-200a (miR-200a) could target Keap1 mRNA and promote degradation of Keap1 mRNA, resulting in Nrf2 activation. However, the role of miR-200a in DOX-related cardiotoxicity remained unclear. Our study is aimed at investigating the effect of miR-200a on DOX-induced cardiotoxicity in mice. For cardiotropic expression, male mice received an injection of an adeno-associated virus 9 (AAV9) system carrying miR-200a or miR-scramble. Four weeks later, mice received a single intraperitoneal injection of DOX at 15 mg/kg. In our study, we found that miR-200a mRNA was the only microRNA that was significantly decreased in DOX-treated mice and H9c2 cells. miR-200a supplementation blocked whole-body wasting and heart atrophy caused by acute DOX injection, decreased the levels of cardiac troponin I and the N-terminal probrain natriuretic peptide, and improved cardiac and adult cardiomyocyte contractile function. Moreover, miR-200a reduced oxidative stress and cardiac apoptosis without affecting matrix metalloproteinase and inflammatory factors in mice with acute DOX injection. miR-200a also attenuated DOX-induced oxidative injury and cell loss in vitro. As expected, we found that miR-200a activated Nrf2 and Nrf2 deficiency abolished the protection provided by miR-200a supplementation in mice. miR-200a also provided cardiac benefits in a chronic model of DOX-induced cardiotoxicity. In conclusion, miR-200a protected against DOX-induced cardiotoxicity via activation of the Nrf2 signaling pathway. Our data suggest that miR-200a may represent a new cardioprotective strategy against DOX-induced cardiotoxicity.

NOX1 Negatively Modulates Fibulin-5 in Vascular Smooth Muscle Cells to Affect Aortic Dissection.

Aortic dissection (AD) diseases are characterized by degeneration of the aortic media. Oxidative stress plays a crucial role in the development of AD. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 (NOX1) deficiency reduces the incidence of aortic dissection induced by angiotensin II, but its mechanism remains to be further elucidated. The expression of Fibulin-5 is decreased in patients with AD, but its upstream mechanism is still unclear. This study was to clarify the relationship between NOX1 and Fibulin-5 in the AD. Results showed that the expressions of NOX1 and Fibulin-5 were increased and decreased in the AD, respectively. Next, by employing gain- and loss-of-function approaches in vitro, NOX1 negatively regulated Fibulin-5 in the vascular smooth muscle cells. Moreover, the blunted activity of NOX1 with VAS2870 could upregulate the expression of Fibulin-5. These findings indicate NOX1 is a negative modulator of Fibulin-5 in the AD.

An observational study on the clinical features of esophageal cancer followed by multiple primary cancers.

AIM: To investigate the nature of multiple primary cancers initiated by esophageal cancer-multiple primary cancers (EC-MPC). PATIENTS & METHODS: SEER data about patients'/tumor characteristics, and survival were analyzed and compared. RESULTS & CONCLUSION: 1727 of 29,733 registered EC patients have EC-MPC. Individuals diagnosed at 60-79 years old, earlier stage and/or moderately differentiated EC were more likely to get EC-MPC. Fewer patients in the EC-MPC group suffered from metastases. Patients in the EC-MPC group showed a longer survival rate and lower EC-specific deaths. Other factors like age, sex, race, tumor differentiation and Tumor, Node, Metastasis stage also affected survival. Radiation can improve survival. EC-MPC patients have some distinct features compared with solitary EC.

BR-INSENSITIVE1 regulates hydrotropic response by interacting with plasma membrane H+-ATPases in Arabidopsis.

Arabidopsis roots sense the moisture gradient in soils and grow toward an area with higher water potential - a process called hydrotropism. Our previous study has shown that the apoplastic proton extrusion in root tips is influenced by brassinosteroids (BRs) receptor BR-INSENSITIVE1 (BRI1) and is crucial for hydrotropic response in Arabidopsis. Here we show that BRI1 interacts directly not only with Arabidopsis plasma membrane H+-ATPase 2 (AHA2) but also with Arabidopsis plasma membrane H+-ATPase 7 (AHA7). Therefore, BRI1 may affect hydrotropic response via regulating the activities of AHA2 and AHA7.

Scorpion Venom Active Polypeptide May Be a New External Drug of Diabetic Ulcer.

BACKGROUND: The epidermal growth factor (EGF) is recognized medicine of therapy in ulcer. However, its efficacy has been challenged. We compared scorpion venom active polypeptide and EGF of therapeutic effects in diabetic ulcer. METHODS: The scorpion venom active polypeptide is made into gel. Fourteen diabetic SD rats were randomly divided into scorpion peptide gel group (SPG group) and EGF group. Before treatment, the rat model of diabetic ulcer was created. The levels of IL-1, IL-6, IL-8, and TNF-α in the wound tissue were measured at different time points during the treatment, secretions of wound were collected for bacterial culture, and the wound healing was recorded. RESULTS: Wound healing was faster in SPG group compared to EGF group (3 weeks versus 5 weeks, t-test, p = 0.032). The levels of IL-1, IL-6, IL-8, and TNF-α were not statistically different when the wounds were formed but showed significant differences from the 2nd to the 5th week between two groups. The infection rate was higher in the EGF group (42.86% versus 0, Chi-square test, p = 0.025). CONCLUSIONS: Scorpion venom active polypeptide shortens wound healing with a stronger anti-inflammation and antibacterial effect and may be a new and effective topical drug for the treatment of diabetic ulcers.

Assessing Serum Levels of ADAMTS1 and ADAMTS4 as New Biomarkers for Patients with Type A Acute Aortic Dissection.

BACKGROUND Type A AAD, a serious cardiovascular emergency requiring urgent surgery, is the most common and serious AAD. The aim of this study was to investigate the diagnostic value of ADAMTS1 and ADAMTS4 in patients with type A acute aortic dissection (AAD). MATERIAL AND METHODS Immunohistochemistry and qRT-PCR were used to evaluate the protein and mRNA expression levels of ADAMTS1 and ADAMTS4 in 14 type A acute aortic dissection (AAD) tissues and 10 control aortic tissues. Serum ADAMTS1 and ADAMTS4 expression levels in 74 patients with type A AAD, 36 patients with hypertension (HPT), and 34 healthy donors were examined by ELISA. The diagnostic value of serum ADAMTS1 and ADAMTS4 were determined by receiver operator characteristic curve (ROC). Furthermore, the dynamic change of serum ADAMTS1, ADAMTS4, D-dimer, and CRP were detected before and after surgery at different time-points in 14 patients with type A AAD. RESULTS ADAMTS1 and ADAMTS4 protein and mRNA expression levels were found to be significantly higher in 14 type A AAD tissues (p<0.0001) compared with 10 control tissues. Serum ADAMTS1 and ADAMTS4 levels were significant higher in patients with type A AAD than those in the HPT and HD group (p<0.0001 for both). The AUC value, sensitivity, and specificity of ADAMTS1 were 0.9710 (95% CI: 0.9429 to 0.9991), 87.84%, and 97.06%, respectively, and those of ADAMTS4 were 0.9893 (95% CI: 0.9765 to 1.002), 94.59%, and 97.06%, respectively. In addition, serum ADAMTS4 level was gradually decreased with the time extension after surgery, similar to D-dimer change. CONCLUSIONS These data suggest that measurement of serum ADAMTS1 and ADAMTS4 levels could be potential diagnostic biomarkers for type A AAD, and ADAMTS4 might be a risk factor associated with type A AAD.

MDG­1 inhibits H2O2­induced apoptosis and inflammation in human umbilical vein endothelial cells.

MDG­1, a water­soluble polysaccharide extracted from Ophiopogon japonicus, has been reported to serve a role in antimyocardial ischemia by protecting cardiomyocytes from hypoxia/reoxygenation­induced damage. However, it remains unknown whether MDG­1 protects human umbilical vein endothelial cells (HUVECs) against oxidative stress­induced damage. In the present study, HUVECs were treated with hydrogen peroxide (H2O2) to establish an oxidative stress­induced cell injury model. Treatment of HUVECs with different concentrations of H2O2 significantly attenuated cell viability and increased cell apoptosis in a time and dose­dependent manner. Pretreatment with MDG­1 markedly reduced H2O2­induced cell death, ROS generation and inflammatory factor secretion. In addition, pretreatment with MDG­1 decreased the expression levels of proapoptotic proteins BCL2 associated X (Bax) and caspase­3, while it increased the expression levels of the antiapoptotic protein BCL2 apoptosis regulator (Bcl­2), compared with H2O2 treatment alone. Taken together, the present data suggest that MDG­1 protected HUVECs against H2O2­induced apoptosis and inflammation through inhibition of Bax/Bcl­2 protein ratio, caspase­3 expression, and inflammatory factor secretion. This study provides a potential application for MDG­1 in the treatment of cardiovascular disease.

The role of bradykinin in lung ischemia-reperfusion injury in a rat lung transplantation model

ABSTRACT PURPOSE: To investigate the role of bradykinin in a rat lung transplantation (LTx) model and preliminarily discuss the relationship between bradykinin and CD26/DPP-4. METHODS: Rats were randomly divided into four groups: Control (CON), Sham, low potassium dextranglucose (LPD), and AB192 (n=15/group). Orthotopic single LTx was performed in the LPD and AB192 groups. The donor lungs were flush-perfused and preserved with low potassium dextranglucose (LPD) or LPD+CD26/DPP-4 catalytic inhibitor (AB192). LTx was performed after 18 h cold ischemia time and harvested two days post-LTx. Blood gas analysis (PO2), wet/dry weight ratio (W/D), myeloperoxidase activity (MPO), and lipid peroxidation (MDA) were analyzed at 48 hr after transplantation. Immunohistochemical (IHC) analysis was performed in the same sample and validated by Western-Blot. RESULTS: Compared to the LPD group, the AB192 group showed higher PO2, lower W/D ratio, and decreased MPO and MDA. IHC studies showed strong bradykinin β2 receptor (B2R) staining in the LPD group, especially in inflammatory cells, alveolar macrophages, and respiratory epithelial cells. Expression of B2R by Western-Blot was significantly different between the AB192 and LPD groups. CONCLUSION: Bradykinin may be a competitive substrate of DPP-4, and decreased bradykinin levels may enhance protective effects against ischemia/reperfusion injury during LTx.