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Defective or insufficient bone repair and regeneration are common in patients as a result of major trauma or severe disease. Cell therapy with periosteal mesenchymal progenitors, which can be limited in severe injury, serves as a promising approach; however, its efficacy is limited due to a repair-hostile ischemic tissue microenvironment after traumatic fracture. Here we report that plasminogen (Plg), a factor that is upregulated in these environments, is critical for fracture healing. Plg knockout mice had impaired trabecular and cortical bone structure and exhibited delayed and incomplete fracture healing. Interestingly, Plg deficiency greatly reduced the thickness of expanded periosteum, suggesting a role of Plg in periosteal mesenchymal progenitor-mediated bone repair. In culture, Plg increased cell proliferation and migration in periosteal mesenchymal progenitors and inhibited cell death under ischemic conditions. Mechanistically, we revealed that Plg cleaved and activated Cyr61 to regulate periosteal progenitor function. Thus, our study uncovers a cellular mechanism underlying fracture healing, by which Plg activates Cyr61 to promote periosteal progenitor proliferation, survival, and migration and improves bone repair after fracture. Targeting Plg may offer a rational and effective therapeutic opportunity for improving fracture healing. © 2021 American Society for Bone and Mineral Research (ASBMR).

Stem cell transplantation has emerged as a promising strategy in regenerative medicine. However, the poor survival and persistence of the transplanted cells, including mesenchymal stem cells (MSCs), in the hostile ischemic microenvironments represents a major therapeutic barrier. Here we report that plasminogen (Plg) stimulated MSC functions and promoted MSC survival during tissue repair after ischemia. Genetic Plg ablation abolished MSC survival, migration, and proliferation in mouse ischemic limbs, and abrogated MSC-mediated blood reperfusion, neovascularization, and tissue repair after ischemia, suggesting a critical role for Plg in MSC-mediated tissue repair. Furthermore, multiplex cytokine array analysis identified that Plg cleaved and activated cysteine-rich protein 61 (Cyr61), an ECM-associated growth factor, to stimulate MSC survival and migration. Overexpression with truncated Cyr61 in MSCs rescued blood reperfusion after hind limb ischemia in Plg-deficient mice. Finally, Plg-mediated Cyr61 cleavage promoted endothelial cell migration and neovascularization in vitro and in vivo. Our study reveals that Plg promotes MSC survival, persistence, and paracrine effects and improves postischemic neovascularization and tissue repair through Cyr61 cleavage and activation. Thus, targeting Plg/Cyr61 may offer exciting therapeutic opportunities for strengthening MSC therapy in ischemic diseases., Plasminogen promotes mesenchymal stem cell function and improves post-ischemic neovascularization and tissue repair through cysteine-rich protein 61 activation.

Background Coronary atherosclerotic heart disease (CHD) is the most common cardiovascular disease and has become a leading cause of death globally. Various molecular typing methods are available for the diagnosis and treatment of tumors. However, molecular typing results are not routinely used for CHD. Methods and Results Aiming to uncover the underlying molecular features of different types of CHD, we screened the differentially expressed genes (DEGs) associated with CHD based on the Gene Expression Omnibus (GEO) data and expanded those with the NCBI‐gene and OMIM databases to finally obtain 2021 DEGs. The weighted gene co‐expression analysis (WGCNA) was performed on the candidate genes, and six distinctive WGCNA modules were identified, two of which were associated with CHD. Moreover, DEGs were mined as key genes for co‐expression based on the module network relationship. Furthermore, the differentially expressed miRNAs in CHD and interactions in the database were mined in the GEO data set to build a multifactor regulatory network of key genes for co‐expression. Based on the network, the CHD samples were further classified into five clusters and we defined FTH1, HCAR3, RGS2, S100A9, and TYROBP as the top genes of the five subgroups. Finally, the mRNA levels of FTH1, S100A9, and TYROBP were found to be significantly increased, while the expression of HCAR3 was decreased in the blood of CHD patients. We did not detect measurable levels of RGS2. Conclusion The screened core clusters of genes may be a target for the diagnosis and treatment of CHD as a molecular typing module., WGCNA was performed on CHD‐related datasets downloaded from online datebases to screened out DEGs and a multi‐factor regulatory network of key genes for co‐expression. Based on the aforementioned network, the CHD samples were further classified into 5 clusters and we defined FTH1, HCAR3, RGS2, S100A9 and TYROBP as individually top genes of 5 subgroups.

Background and aims We examined whether the inflammation resolution mediator lipoxin A4 (LXA4) inhibits foam cell formation and oxidized low-density lipoprotein (oxLDL)-induced apoptotic signaling in macrophages and the role of circulating/local LXA4 biosynthesis in atherogenesis. Methods LXA4 levels were measured by enzyme-linked immunosorbent assay. Dil-oxLDL and Dil-acLDL binding to and uptake by macrophages were evaluated by flow cytometry. Apoptosis was evaluated by TUNEL and Annexin V/PI assays. Results Circulating LXA4 levels in patients with coronary artery disease were much higher than those in respective controls. Local LXA4 levels were much lower in rabbit atherosclerotic vessel walls. Interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) were elevated in atherosclerotic vessels. After the inflammatory stimulus (IFN-γ, TNF-α, and C-reactive protein), LXA4 synthesis decreased significantly in foam cells. LXA4 dose-dependently suppressed the expression of the cholesterol uptake genes CD36 and SR-A in macrophages, which was blocked by the LXA4 receptor antagonist BOC-2. LXA4 also inhibited oxLDL-induced CD36 upregulation, Dil-oxLDL uptake, and foam cell formation. Furthermore, LXA4 inhibited the oxLDL-activated c-Jun N-terminal kinase pathway and reduced oxLDL-induced macrophage apoptosis by inhibiting caspase-3 activation and restoring the mitochondrial membrane potential. Conclusions We found that LXA4 inhibited foam cell formation, oxLDL-induced inflammation, and apoptotic signaling in macrophages. Insufficient levels of the anti-inflammatory pro-resolution molecule LXA4 were found in rabbit atherosclerotic arteries, which might contribute to preventing inflammation resolution during atherogenesis.

Telemedicine interventions may be associated with reductions in hospital admission rate and mortality in patients with heart failure (HF). The present study is an updated analysis (as of June 30, 2016) of randomized controlled trials, where patients with HF underwent telemedicine care or the usual standard care. Data were extracted from 39 eligible studies for all-cause and HF-related hospital admission rate, length of stay, and mortality. The overall all-cause mortality (pooled OR=0.80, 95% CI 0.71 to 0.91, p

Aims Adverse cardiovascular effects induced by peroxisome proliferator activator receptor-γ (PPAR-γ) activation were observed in clinical setting. But the underlying mechanism is unclear. Now, transgenic mice with cardiac specific peroxisome proliferator activator receptor-γ overexpression (TG-PPAR-γ) were used to explore the possible mechanisms. Materials and methods Cardiac tissues from TG-PPAR-γ mice, a PPAR-γ over-expressing human cardiomyocyte line AC16 cell, and PPAR-γ agonist-treated primary cardiomyocytes were used to evaluate the expression of cardiac calcium regulatory proteins as sarcoplasmic reticulum Ca 2 + ATPase, Na + /Ca 2 + exchanger 1, ryanodine receptor 2 and phospholamban. Intracellular Ca 2 + levels were also examined by flow cytometry and confocal microscopy with Fluo-4/AM in these cells. Key findings In this study, frequent ventricular premature contraction and polymorphic ventricular tachycardia were observed in TG-PPAR-γ but not in wild-type mice. Besides, we found the calcium regulatory proteins expression were higher in the TG-PPAR-γ mice, PPAR-γ overexpressing human cardiomyocyte line AC16 cell and PPAR-γ agonist-treated primary cardiomyocytes than the control group respectively. In addition, an increase of intracellular calcium levels and CaMKII δ expression in PPAR-γ overexpression and PPAR-γ activation group. Moreover, Inhibition of CaMKII δ could improve the intracellular calcium levels and reduce the occurrence of ventricular arrhythmia. Significance PPAR-γ over-expression perturbs the intracellular calcium homeostasis in cardiomyocytes which contribute to the ventricular arrhythmias and cardiac sudden death in TG-PPAR-γ mice.

Objective: To investigate the significance of hemoglobin A1c (HbA1c) in cardiovascular and metabolic risk stratification among diabetes and non-diabetes in southern Chinese. Methods: Indigenous adults (aged more than or equal to 35 years) without known diabetes were enrolled in the cross-sectional survey. According to oral glucose tolerance test (OGTT), participants were categorized into OGTT-negative group and OGTT-positive group. Cardiovascular and metabolic risk profile was compared between different HbA1c levels (≥ 6.5% vs. < 6.5%) in each group. Results: The prevalence of OGTT-diagnosed diabetes was 6.45% (422/6540). In OGTT-negative group, subjects with HbA1c ≥ 6.5% were older, had higher prevalence of coronary heart disease, current smoking, hypertension, obesity and abdominal obesity. They also had higher body weight, waist–hip ratio, body mass index, glucose levels (fasting plasma glucose, 2-hour plasma glucose and HbA1c), and lipid levels (total cholesterol and low density lipoprotein cholesterol). In OGTT-positive group, patients with HbA1c ≥ 6.5% identified less cardiovascular and metabolic risk file than that in OGTT-negative group. Conclusions: Subjects with HbA1c ≥ 6.5% have more unfavorable cardiovascular and metabolic risk profile than those with HbA1c < 6.5%, especially in OGTT-negative population. More attention should be paid to this subgroup in clinical practice.

Objectives Yes-associated protein (YAP) has been reported to regulate cell proliferation and differentiation. We aimed to characterize the role of YAP in angiotensin II (Ang II)-induced hypertensive vascular remodelling (HVR) and vascular smooth muscle cells (VSMCs) phenotypic modulation and to explore the underlying mechanisms. Materials and methods An HVR rat model was established by continuous Ang II infusion for 2 weeks. Western blotting, qRT-PCR, and confocal microscopy were conducted to assess YAP expression. YAP-shRNA interfering plasmid and adenovirus were constructed to knock down YAP. We used cell proliferation and migration assays, accompanied by pathway inhibitors, to evaluate the biological function and underlying mechanisms. Results Ang II upregulated YAP expression in the media of carotid artery; however, in vivo YAP silencing significantly mitigated HVR, independent of the blood pressure level. Ang II upregulated YAP expression and promoted YAP nuclear accumulation in a dose- and time-dependent manner in rat VSMCs. YAP knockdown ameliorated Ang II-induced VSMCs phenotypic modulation. The regulation of YAP by Ang II could be blocked by pretreatment with angiotensin receptor type 1 antagonist losartan or F-actin depolymerizing agent latrunculin B but not the AT2R antagonist PD 123319. Disrupting the YAP-TEA domain (TEAD) interaction with verteporfin inhibited Ang II-induced VSMCs phenotypic modulation. Conclusions Yes-associated protein mediated angiotensin II-induced VSMCs phenotypic modulation and vascular remodelling. YAP is a potential therapeutic target for HVR beyond blood pressure control.

Objective The objective of this study is to determine the diagnostic threshold of HbA1c for diabetes and the impact of using it on diabetes prevalence. Methods A population-based stratified study was conducted in 2010 among community-dwelling adults aged ≥ 35 years in southern China. Participants without previously-diagnosed diabetes (PDD) took oral glucose tolerance test (OGTT) and HbA1c assay. HbA1c diagnostic threshold was determined by receiver operating characteristic curve. Results A total of 6989 participants with mean age of 52 years were recruited. The area under curve of HbA1c was 0.903 (95% CI: 0.883–0.922), with optimal cut-off value at 6.25% (sensitivity 75.6% and specificity 91.9%). There were 449 (6.42%) patients with PDD and 422 (6.04%), 815 (11.66%) and 918 (13.13%) new cases diagnosed by OGTT, HbA1c ≥ 6.25% or either, respectively. When either HbA1c or OGTT was used, newly-diagnosed diabetes prevalence increased by 117.4%. Conclusions Diabetes is prevalent in southern China. Near half of the patients go undetected with current diagnostic criteria. HbA1c ≥ 6.25% may be the diagnostic threshold value but needs further verification. The introduction of HbA1c threshold into diabetes diagnosis in China will cause a substantial increase in diabetes prevalence and great challenge on the public healthcare system.