A novel role of kallikrein-related peptidase 8 in the pathogenesis of diabetic cardiac fibrosis.

Rationale: Among all the diabetic complications, diabetic cardiomyopathy, which is characterized by myocyte loss and myocardial fibrosis, is the leading cause of mortality and morbidity in diabetic patients. Tissue kallikrein-related peptidases (KLKs) are secreted serine proteases, that have distinct and overlapping roles in the pathogenesis of cardiovascular diseases. However, whether KLKs are involved in the development of diabetic cardiomyopathy remains unknown.The present study aimed to determine the role of a specific KLK in the initiation of endothelial-to-mesenchymal transition (EndMT) during the pathogenesis of diabetic cardiomyopathy. Methods and Results-By screening gene expression profiles of KLKs, it was found that KLK8 was highly induced in the myocardium of mice with streptozotocin-induced diabetes. KLK8 deficiency attenuated diabetic cardiac fibrosis, and rescued the impaired cardiac function in diabetic mice. Small interfering RNA (siRNA)-mediated KLK8 knockdown significantly attenuated high glucose-induced endothelial damage and EndMT in human coronary artery endothelial cells (HCAECs). Diabetes-induced endothelial injury and cardiac EndMT were significantly alleviated in KLK8-deficient mice. In addition, transgenic overexpression of KLK8 led to interstitial and perivascular cardiac fibrosis, endothelial injury and EndMT in the heart. Adenovirus-mediated overexpression of KLK8 (Ad-KLK8) resulted in increases in endothelial cell damage, permeability and transforming growth factor (TGF)-ß1 release in HCAECs. KLK8 overexpression also induced EndMT in HCAECs, which was alleviated by a TGF-ß1-neutralizing antibody. A specificity protein-1 (Sp-1) consensus site was identified in the human KLK8 promoter and was found to mediate the high glucose-induced KLK8 expression. Mechanistically, it was identified that the vascular endothelial (VE)-cadherin/plakoglobin complex may associate with KLK8 in HCAECs. KLK8 cleaved the VE-cadherin extracellular domain, thus promoting plakoglobin nuclear translocation. Plakoglobin was required for KLK8-induced EndMT by cooperating with p53. KLK8 overexpression led to plakoglobin-dependent association of p53 with hypoxia inducible factor (HIF)-1α, which further enhanced the transactivation effect of HIF-1α on the TGF-ß1 promoter. KLK8 also induced the binding of p53 with Smad3, subsequently promoting pro-EndMT reprogramming via the TGF-ß1/Smad signaling pathway in HCAECs. The in vitro and in vivo findings further demonstrated that high glucose may promote plakoglobin-dependent cooperation of p53 with HIF-1α and Smad3, subsequently increasing the expression of TGF-ß1 and the pro-EndMT target genes of the TGF-ß1/Smad signaling pathway in a KLK8-dependent manner. Conclusions: The present findings uncovered a novel pro-EndMT mechanism during the pathogenesis of diabetic cardiac fibrosis via the upregulation of KLK8, and may contribute to the development of future KLK8-based therapeutic strategies for diabetic cardiomyopathy.

Effect of competence health cultivation on the prevention and control of inadvertent perioperative hypothermia.

OBJECTIVE To explore the feasibility of health competence cultivation on the prevention and control of Inadvertent Perioperative Hypothermia (IPH). METHODS Patients with expected spinal surgery were divided into group A and group B by the random number method. Group B followed routine IPH management, and health training measures for performance and ability were implemented in Group A. The scores of the health competence questionnaire, the temperature at different times, IPH complications, and hospitalization for the two groups were observed and compared. RESULTS The main evaluation indexes, such as the health competence questionnaire score, temperature fluctuations, and IPH complications, during the perioperative period in group A were significantly better than those in group B (p < 0.05). The indexes of anesthesia, total hospital expenses, and health service satisfaction in group A were also significantly better than those in group B, which shows the advantages of cultivating health capabilities in both doctors and patients. CONCLUSION Through health competence cultivation and feasible health management measures, the medical staff can improve the quality of IPH prevention and management.

Effect of competence health cultivation on the prevention and control of inadvertent perioperative hypothermia

SUMMARY OBJECTIVE To explore the feasibility of health competence cultivation on the prevention and control of Inadvertent Perioperative Hypothermia (IPH). METHODS Patients with expected spinal surgery were divided into group A and group B by the random number method. Group B followed routine IPH management, and health training measures for performance and ability were implemented in Group A. The scores of the health competence questionnaire, the temperature at different times, IPH complications, and hospitalization for the two groups were observed and compared. RESULTS The main evaluation indexes, such as the health competence questionnaire score, temperature fluctuations, and IPH complications, during the perioperative period in group A were significantly better than those in group B (p < 0.05). The indexes of anesthesia, total hospital expenses, and health service satisfaction in group A were also significantly better than those in group B, which shows the advantages of cultivating health capabilities in both doctors and patients. CONCLUSION Through health competence cultivation and feasible health management measures, the medical staff can improve the quality of IPH prevention and management.

RESUMO OBJETIVO Explorar a viabilidade do cultivo da competência em saúde na prevenção e controle da hipotermia perioperativa inadvertida (IPH). MÉTODOS Pacientes com cirurgia espinhal marcada foram divididos em dois grupos, A e B, pelo método de números aleatórios. O grupo B foi conduzido com base na gestão rotineira para prevenção de IPH; já no grupo A, foram implementadas medidas de treinamento em competência de saúde. As pontuações do questionário sobre competência em saúde, a temperatura aferida em diferentes momentos, complicações relacionadas à IPH e hospitalização dos dois grupos foram observadas e comparadas. RESULTADOS Os principais índices de avaliação, como a pontuação do questionário sobre competência em saúde, a variação de temperatura e as complicações relacionadas à IPH durante o período perioperatório foram significativamente melhores no grupo A do que no grupo B (p<0,05). Os índices de anestesia, despesas hospitalares totais e satisfação com o serviço de saúde também foram significativamente melhores no grupo A do que no B, o que demonstra as vantagens do cultivo da competência de saúde tanto em médicos como em pacientes. CONCLUSÃO Por meio do cultivo de competências de saúde e de medidas viáveis de gestão da saúde, a equipe médica pode melhorar a qualidade da prevenção e gestão da IPH.

Exercise training ameliorates bleomycin-induced epithelial mesenchymal transition and lung fibrosis through restoration of H2 S synthesis.

AIMS: Clinical trials have shown the beneficial effects of exercise training against pulmonary fibrosis. This study aimed to investigate whether prophylactic intervention with exercise training attenuates lung fibrosis via modulating endogenous hydrogen sulphde (H2 S) generation. METHODS: First, ICR mice were allocated to Control, Bleomycin, Exercise, and Bleomycin + Exercise groups. Treadmill exercise began on day 1 and continued for 4 weeks. A single intratracheal dose of bleomycin (3 mg/kg) was administered on day 15. Second, ICR mice were allocated to Control, Bleomycin, H2 S, and Bleomycin + H2 S groups. H2 S donor NaHS (28 µmol/kg) was intraperitoneally injected once daily for 2 weeks. RESULTS: Bleomycin-treated mice exhibited increased levels of collagen deposition, hydroxyproline, collagen I, transforming growth factor (TGF)-ß1, Smad2/Smad3/low-density lipoprotein receptor-related proteins (LRP-6)/glycogen synthase kinase-3ß (GSK-3ß) phosphorylation, and Smad4/ß-catenin expression in lung tissues (P < 0.01), which was alleviated by exercise training (P < 0.01 except for Smad4 and phosphorylated GSK-3ß: P < 0.05). Bleomycin-induced lung fibrosis was associated with increased α smooth muscle actin (α-SMA) and decreased E-cadherin expression (P < 0.01). Double immunofluorescence staining showed the co-localization of E-cadherin/α-SMA, indicating epithelial-mesenchymal transition (EMT) formation, which was ameliorated by exercise training. Moreover, exercise training restored bleomycin-induced downregulation of cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE) expression, as well as H2 S generation in lung tissue (P < 0.01). NaHS treatment attenuated bleomycin-induced TGF-ß1 production, activation of LRP-6/ß-catenin signalling, EMT and lung fibrosis (P < 0.01 except for ß-catenin: P < 0.05). CONCLUSION: Exercise training restores bleomycin-induced downregulation of pulmonary CBS/CSE expression, thus contributing to the increased H2 S generation and suppression of TGF-ß1/Smad and LRP-6/ß-catenin signalling pathways, EMT and lung fibrosis.