The role of deubiquitinases in cardiac disease.

Deubiquitinases are a group of proteins that identify and digest monoubiquitin chains or polyubiquitin chains attached to substrate proteins, preventing the substrate protein from being degraded by the ubiquitin-proteasome system. Deubiquitinases regulate cellular autophagy, metabolism and oxidative stress by acting on different substrate proteins. Recent studies have revealed that deubiquitinases act as a critical regulator in various cardiac diseases, and control the onset and progression of cardiac disease through a board range of mechanism. This review summarizes the function of different deubiquitinases in cardiac disease, including cardiac hypertrophy, myocardial infarction and diabetes mellitus-related cardiac disease. Besides, this review briefly recapitulates the role of deubiquitinases modulators in cardiac disease, providing the potential therapeutic targets in the future.

Factors affecting the primary patency of native arteriovenous fistulas after ultrasound-guided percutaneous transluminal angioplasty.

OBJECTIVE: By analyzing the clinical history, laboratory test indexes, and intraoperative ultrasound imaging data of patients receiving ultrasound-guided percutaneous transluminal angioplasty (UG-PTA) for the first time, the application value of UG-PTA in the treatment of peripheral stenosis of autogenous arteriovenous fistula (AVF) and the related factors affecting postoperative patency were investigated. METHODS: A total of 381 patients with dysfunction of radio-cephalic AVF were treated with UG-PTA from June 2017 to September 2019. According to the inclusion and exclusion criteria, 199 patients were included in this study. Baseline characteristics of patients, including demographic, clinical, and laboratory data, were collected. Kaplan-Meier's survival curve was used to demonstrate the cumulative primary patency rate of UG-PTA. Univariate and multivariate Cox regression analysis was performed on clinical, anatomic, biochemical, and medication variables to identify the predictors of postintervention primary patency. RESULTS: The early technical success rate of UG-PTA was 98.4% (375/381). One hundred and ninety-nine patients, with an average age of 52.9 years, were analyzed, 97 of whom were males (48.7%). The median follow-up duration was 21 months. No major complication was observed. Postintervention primary patency rates were 87.7%, 75.8%, and 60.0% at 6, 12, and 24 months, respectively. A previously failed AVF (HR, 1.935, 95% CI 1.071-3.494; p = .029) and an increased level of parathyroid hormone (HR per 100 pg/mL increase, 1.105; 95% CI 1.014-1.203; p = .004) were identified as independent negative predictors of primary patency of UG-PTA. CONCLUSIONS: UG-PTA is a safe and effective method for the treatment of peripheral stenosis of AVF. Previously failed AVF and elevated parathyroid hormone levels are associated with lower primary patency rate.

USP25-PKM2-glycolysis axis contributes to ischemia reperfusion-induced acute kidney injury by promoting M1-like macrophage polarization and proinflammatory response.

M1-like macrophages have been reported to play critical roles in acute kidney injury (AKI). Here, we elucidated the role of ubiquitin-specific protease 25 (USP25) in M1-like macrophages polarization and AKI. High USP25 expression was correlated with a decline in renal function in patients with acute kidney tubular injury and in mice with AKI. In contrast, USP25 knockout reduced M1-like macrophage infiltration, suppressed M1-like polarization, and improved AKI in mice, indicating that USP25 was necessary for M1-like polarization and proinflammatory response. Immunoprecipitation assay and liquid chromatography-tandem mass spectrometry showed that the M2 isoform of pyruvate kinase, muscle (PKM2) was a target substrate of USP25. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated the USP25 regulated aerobic glycolysis and lactate production during M1-like polarization via PKM2. Further analysis showed that the USP25-PKM2-aerobic glycolysis axis positively regulated M1-like polarization and exacerbated AKI in mice, providing potential therapeutic targets for AKI treatment.

Oxidative phosphorylation promotes vascular calcification in chronic kidney disease.

Metabolism has been reported to associate with the progression of vascular diseases. However, how vascular calcification in chronic kidney disease (CKD) is regulated by metabolic status remains poorly understood. Using a model of 5/6 nephrectomy, we demonstrated that the aortic tissues of CKD mice had a preference for using oxidative phosphorylation (OXPHOS). Both high phosphate and human uremic serum-stimulated vascular smooth muscle cells (VSMCs) had enhanced mitochondrial respiration capacity, while the glycolysis level was not significantly different. Besides, 2-deoxy-d-glucose (2-DG) exacerbated vascular calcification by upregulating OXPHOS. The activity of cytochrome c oxidase (COX) was higher in the aortic tissue of CKD mice than those of sham-operated mice. Moreover, the expression levels of COX15 were higher in CKD patients with aortic arch calcification (AAC) than those without AAC, and the AAC scores were correlated with the expression level of COX15. Suppressing COX sufficiently attenuated vascular calcification. Our findings verify the relationship between OXPHOS and calcification, and may provide potential therapeutic approaches for vascular calcification in CKD.

High-Phosphate-Stimulated Macrophage-Derived Exosomes Promote Vascular Calcification via let-7b-5p/TGFBR1 Axis in Chronic Kidney Disease.

Although macrophage infiltration has been proven to increase calcified artery media in chronic kidney disease (CKD) patients, the mechanism by which macrophages are involved in vascular calcification (VC) progression remains unclear. Taking advantage of miRNA-seq, RNA-seq, dual-luciferase reporter assay, qRT-PCR, and arteries from CKD patients as well as CKD mouse models, we identified that high-phosphate-stimulated macrophage-derived exosomes (Mexo-P) suppressed let-7b-5p expression in VSMCs, which further upregulated TGFBR1. Moreover, gain-and-loss-of-function assays were used to determine the regulatory effects and downstream mechanism of let-7b-5p and TGFBR1 on VC. Mechanically, Mexo-P induced VSMC TGFBR1 upregulation by suppressing let-7b-5p, which further amplifies SMAD3/RUNX2 signaling and thereby contributes to VC. Our findings indicate that macrophage-derived exosomes promote CKD-associated VC through the let-7b-5p/TGFBR1 axis in high-phosphate conditions. Our study provides insight into macrophages associated with VC, which might be potential therapeutical targets for VC.