Cardiac Fibroblast Activation Induced by Oxygen-Glucose Deprivation Depends on the HIF-1α/miR-212-5p/KLF4 Pathway.

It is widely accepted that miRNAs play an important role in the pathogenesis of myocardial fibrosis. This study aimed to identify a new pathway of miR-212-5p in the activation of human cardiac fibroblasts (HCFs) induced by oxygen-glucose deprivation (OGD). First, we found that KLF4 protein was markedly decreased in OGD-induced HCFs. Then, bioinformatics analysis and verification experiments were used to identify the existence of an interaction of KLF4 with miR-212-5p. Functional experiments indicated that OGD significantly upregulated the expression of hypoxia inducible factor-1 alpha (HIF-1α) in HCFs, which positively regulated miR-212-5p transcription by binding to its promoter. MiR-212-5p inhibited the expression of Krüppel-like factor 4 (KLF4) protein by binding to the 3' untranslated coding regions (UTRs) of KLF4 mRNA. Inhibition of miR-212-5p effectively inhibited the activation of OGD-induced HCFs by upregulating KLF4 expression and inhibited cardiac fibrosis in vivo and in vitro.

Impact of Iodinated Contrast Media in Patients Received Percutaneous Coronary Intervention: Focus on Thyroid Disease.

Background: With the rapid advance in percutaneous coronary intervention (PCI) technology, patients absorb large volume of iodinated contrast media (ICM). Recent studies suggested that ICM may lead to hyperthyroidism, but the association between ICM volume and thyroid is still unclear. We sought to evaluate the long-term influence of ICM on thyroid dysfunction and disease in patients received PCI. Methods: This single-center retrospective study included consecutive coronary artery disease (CAD) patients. A covariance (ANCOVA) model was performed to evaluate the change of serum TSH, FT3 and FT4 before and one-year after the PCI procedure. Restricted cubic splines and logistic regression were performed to evaluate the association between ICM volume and thyroid disease. Results: 2062 patients met inclusion criteria (1381 patients in the low-volume group and 681 patients in the high-volume group). The high-volume group was 0.238 ± 0.092 pmol/L higher than the low-volume group (P = 0.010) in the serum FT4. Restricted cubic splines show that there were linear dose-response relationships for ICM volume and composite endpoint and hyperthyroidism. In all models, there were significant differences in composite endpoint between the two groups. (OR 1.75, 95% CI (1.05, 2.92), P = 0.032, OR 1.73, 95% CI (1.01-2.96), P= 0.032 and OR 1.83, 95% CI (1.09-3.06), P= 0.022, respectively). The positive results were also showed for hyperthyroidism in all models (OR 2.35, 95% CI (1.14-4.84), P = 0.021, OR 10.36, 95% CI (1.20-89.00), P = 0.033 and OR 2.35, 95% CI (1.13-4.87), P = 0.022, respectively). Conclusion: The present analysis gives an overview that ICM volume is associated with an increased risk of thyroid dysfunction and thyroid disease.

SIRT1 ameliorates renal ischemia-reperfusion injury through suppressing endoplasmic reticulum stress-mediated autophagy.

BACKGROUND: Renal ischemia-reperfusion (IR) injury is a therapeutic challenge for surgeons. Sirtuin 1 (SIRT1) is an NAD+-dependent deacetylase that plays a vital role in modulating cellular senescence and aging. In this study, we determined whether SIRT1 upregulation could alleviate renal IR injury and the underlying mechanism. METHODS: A renal IR model was induced in male C57BL/6 mice. Blood urea nitrogen and serum creatinine were evaluated as markers of kidney function, and renal injury was assessed by pathological examination. The inflammatory milieu was analyzed by real-time RT-PCR and myeloperoxidase immunofluorescence assays. Western blotting was used to quantify SIRT1 protein expression, endoplasmic reticulum stress, and autophagy. RESULTS: SIRT1 was upregulated in renal tissue after IR. Blood analysis and histopathologic examination demonstrated that SIRT1 preserved renal function and reduced renal damage. Further evaluation illustrated that IR induced autophagy and endoplasmic reticulum stress, while SIRT1 upregulation reduced endoplasmic reticulum stress-mediated autophagy levels. CONCLUSIONS: SIRT1 upregulation protects the kidney against IR-induced injury by inhibiting endoplasmic reticulum stress-mediated autophagy.

SAHA, an HDAC inhibitor, attenuates antibody-mediated allograft rejection.

BACKGROUND: Antibody-mediated rejection (AMR) is gaining increasing recognition as a critical causative factor contributing to graft loss in organ transplantation. However, current therapeutic options for prevention and treatment of AMR are very limited and ineffective. The impact of epigenetic modification in B-cell function and its involvement in AMR is still yet to be explored. METHODS: The impacts of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on isolated murine B-cell viability, proliferation, apoptosis, expression of surface marker, and secretion of immunoglobulin and interleukin-10 were investigated. In vivo, a murine cardiac transplant model was used to evaluate the effect of SAHA on splenic B-cell subsets and on AMR in Rag1(-/-) recipient mice after reconstitution of allostimulated B cells. RESULTS: SAHA possesses capability to repress B-cell function. Specifically, SAHA is potent to decrease the viability of isolated B cells by inducing apoptosis. SAHA was also found capable of suppressing the expression of B-cell costimulatory molecules and, as a result, addition of SAHA into the cultures attenuated B-cell proliferation and immunoglobulin secretion. In line with these results, administration of SAHA significantly suppressed AMR in Rag1(-/-) recipient mice after reconstitution of allostimulated B cells along with enhanced cardiac allograft survival time. Mechanistic studies revealed that SAHA promotes B-cell secretion of interleukin-10. CONCLUSIONS: Our data support that SAHA could be a promising immunosuppressive agent with potential beneficial effect on prevention and treatment of AMR.

The argument for the use of mizoribine in renal transplantation: a meta-analysis and systemic review.

OBJECTIVE: The aim of this study is to evaluate the efficacy and safety of mizoribine (MZR) for immunosuppressive therapy in renal transplantation. METHODS: A systematic search of the eligible studies that compared MZR with azathioprine (AZA) for post renal transplant immunosuppressive therapy was performed by using MEDLINE, EMBASE, and the Cochrane Library. Meta-analyses were performed to study the pooled effects of relative risk (RR) and weighted mean difference with 95% confidence intervals (CI). RESULTS: A total of 486 participants from seven clinical trials were included. MZR demonstrated comparable efficacy in terms of acute rejection, patient/graft survival, and serum creatinine. However, MZR was associated with a significantly lower incidence of adverse events as compared with AZA (RR 0.39, CI 0.21-0.73, p=0.003). Specifically, recipients receiving MZR suffered from significantly fewer episodes of myelosuppression (RR 0.12, CI 0.02-0.54, p=0.006) and leukopenia (RR 0.20, CI 0.06-0.70, p=0.01). Also, MZR seemed to offer more favorable outcomes in terms of hepatic dysfunction, infection and diabetes, although the differences were not statistically significant. CONCLUSIONS: MZR is a safe, well-tolerated and effective immunosuppressive agent that can be recommended as an alternative to AZA in renal transplant recipients, although further studies are needed to balance its effect with mycophenolate mofetil.