Genetic ablation and pharmacological inhibition of immunosubunit ß5i attenuates cardiac remodeling in deoxycorticosterone-acetate (DOCA)-salt hypertensive mice.

Hypertensive cardiac remodeling is a major cause of heart failure. The immunoproteasome is an inducible form of the proteasome and its catalytic subunit ß5i (also named LMP7) is involved in angiotensin II-induced atrial fibrillation; however, its role in deoxycorticosterone-acetate (DOCA)-salt-induced cardiac remodeling remains unclear. C57BL/6 J wild-type (WT) and ß5i knockout (ß5i KO) mice were subjected to uninephrectomy (sham) and DOCA-salt treatment for three weeks. Cardiac function, fibrosis, and inflammation were evaluated by echocardiography and histological analysis. Protein and gene expression levels were analyzed by quantitative real-time PCR and immunoblotting. Our results showed that after 21 days of DOCA-salt treatment, ß5i expression and chymotrypsin-like activity were the most significantly increased factors in the heart compared with the sham control. Moreover, DOCA-salt-induced elevation of blood pressure, adverse cardiac function, chamber and myocyte hypertrophy, interstitial fibrosis, oxidative stress, and inflammation were markedly attenuated in ß5i KO mice. These findings were verified in ß5i inhibitor PR-957-treated mice. Moreover, blocking of PTEN (the gene of phosphate and tensin homolog deleted on chromosome ten) markedly attenuated the inhibitory effect of ß5i knockout on DOCA-salt-induced cardiac remodeling. Mechanistically, DOCA-salt stress upregulated the expression of ß5i, which promoted the degradation of PTEN and the activation of downstream signals (AKT/mTOR, TGF-ß1/Smad2/3, NOX, and NF-κB), which ultimately led to cardiac hypertrophic remodeling. This study provides new evidence of the critical role of ß5i in DOCA-salt-induced cardiac remodeling through the regulation of PTEN stability, and indicates that the inhibition of ß5i may be a promising therapeutic target for the treatment of hypertensive heart diseases.

CXCL1-CXCR2 axis mediates angiotensin II-induced cardiac hypertrophy and remodelling through regulation of monocyte infiltration.

Aims: Chemokine-mediated monocyte infiltration into the damaged heart represents an initial step in inflammation during cardiac remodelling. Our recent study demonstrates a central role for chemokine receptor CXCR2 in monocyte recruitment and hypertension; however, the role of chemokine CXCL1 and its receptor CXCR2 in angiotensin II (Ang II)-induced cardiac remodelling remain unknown. Methods and results: Angiotensin II (1000 ng kg-1 min-1) was administrated to wild-type (WT) mice treated with CXCL1 neutralizing antibody or CXCR2 inhibitor SB265610, knockout (CXCR2 KO) or bone marrow (BM) reconstituted chimeric mice for 14 days. Microarray revealed that CXCL1 was the most highly upregulated chemokine in the WT heart at Day 1 after Ang II infusion. The CXCR2 expression and the CXCR2+ immune cells were time-dependently increased in Ang II-infused hearts. Moreover, administration of CXCL1 neutralizing antibody markedly prevented Ang II-induced hypertension, cardiac dysfunction, hypertrophy, fibrosis, and macrophage accumulation compared with Immunoglobulin G (IgG) control. Furthermore, Ang II-induced cardiac remodelling and inflammatory response were also significantly attenuated in CXCR2 KO mice and in WT mice treated with SB265610 or transplanted with CXCR2-deficienct BM cells. Co-culture experiments in vitro further confirmed that CXCR2 deficiency inhibited macrophage migration and activation, and attenuated Ang II-induced cardiomyocyte hypertrophy and fibroblast differentiation through multiple signalling pathways. Notably, circulating CXCL1 level and CXCR2+ monocytes were higher in patients with heart failure compared with normotensive individuals. Conclusions: Angiotensin II-induced infiltration of monocytes in the heart is largely mediated by CXCL1-CXCR2 signalling which initiates and aggravates cardiac remodelling. Inhibition of CXCL1 and/or CXCR2 may represent new therapeutic targets for treating hypertensive heart diseases.

Predictors and prognostic implications of left ventricular ejection fraction trajectory improvement in the spectrum of heart failure with reduced and mildly reduced ejection fraction.

BACKGROUND: The latest guidelines emphasize the significance of evaluating the left ventricular ejection fraction (LVEF) trajectory in patients with heart failure (HF). Because patients with HF with reduced ejection fraction (HFrEF) and HF with mildly reduced ejection fraction (HFmrEF) have reduction in systolic function, they might be in a trajectory of LVEF improvement after medical and device-based therapies. While previous studies have primarily focused on LVEF improvement in HFrEF, there is limited research on LVEF trajectory improvement across the spectrum of HFrEF and HFmrEF. This study aimed to assess the determinants and prognostic implications of LVEF trajectory improvement in HFrEF and HFmrEF patients. METHODS: The cohort was classified into the improved group (HFrEF-to-HF with improved ejection fraction (HFimpEF) and HFmrEF-to-HF with preserved ejection fraction (HFpEF)) and the unimproved group (lack of improved group criteria). The primary endpoints were the composite of all-cause mortality or HF hospitalization, all-cause mortality, and HF hospitalization. Predictors of LVEF trajectory improvement were also evaluated. RESULTS: A total 1303 patients were included in the study (improved/unimproved group: n = 497/806). Cox regression analysis showed that the improved group experienced lower risks of prespecified end points than the unimproved group. Multivariate logistic regression analysis showed that atrial flutter, use of spironolactone, and treatment with catheter ablation were associated with LVEF trajectory improvement, while myocardial infarction, prior percutaneous catheter intervention or coronary artery bypass graft, E/e', and left ventricular end-diastolic diameter were identified as negative predictors of LVEF trajectory improvement. In the improved subgroup, the prognosis for the HFrEF-to-HFimpEF and HFmrEF-to-HFpEF was comparable. CONCLUSIONS: LVEF trajectory improvement patients had improved clinical outcomes and it was associated with important clinical, baseline cardiac structure and function, and treatment factors. Outcomes were similar in both HFrEF-to-HFimpEF and HFmrEF-to-HFpEF subgroups. These results suggest that emphasis should be placed on LVEF trajectory improvement to improve the outcomes of this population.

Rational Design of a Cross-Linked Composite Solid Electrolyte for Li-Metal Batteries.

The interfacial problem caused by solid-solid contact is an important issue faced by a solid-state electrolyte (SSE). Herein, a cross-linked composite solid electrolyte (CSE) poly(vinylene carbonate) (PVCA)─ethoxylated trimethylolpropane triacrylate (ETPTA)─Li1.5Al0.5Ge1.5(PO4)3 (LAGP) (PEL) is prepared by in situ thermal polymerization. The ionic conductivity and Li+ transference number (tLi+) of PEL increase significantly due to the addition of LAGP, which can reach 1.011 × 10-4 S cm-1 and 0.451 respectively. The electrochemical stable window is also widened to 4.68 V. Benefiting from the integrated interfacial structure, the assembled coin cell shows low interfacial resistance. The all-solid-state NCM622|PEL|Li coin cell exhibits an initial discharge capacity of 169.7 mA h g-1 and 70% capacity retention over 100 cycles at 0.2 C, demonstrating excellent cycling stability.

Circulating purification of cutting fluid: an overview.

Cutting fluid has cooling and lubricating properties and is an important part of the field of metal machining. Owing to harmful additives, base oils with poor biodegradability, defects in processing methods, and unreasonable emissions of waste cutting fluids, cutting fluids have serious pollution problems, which pose challenges to global carbon emissions laws and regulations. However, the current research on cutting fluid and its circulating purification technique lacks systematic review papers to provide scientific technical guidance for actual production. In this study, the key scientific issues in the research achievements of eco-friendly cutting fluid and waste fluid treatment are clarified. First, the preparation and mechanism of organic additives are summarized, and the influence of the physical and chemical properties of vegetable base oils on lubricating properties is analyzed. Then, the process characteristics of cutting fluid reduction supply methods are systematically evaluated. Second, the treatment of oil mist and miscellaneous oil, the removal mechanism and approach of microorganisms, and the design principles of integrated recycling equipment are outlined. The conclusion is concluded that the synergistic effect of organic additives, biodegradable vegetable base oils and recycling purification effectively reduces the environmental pollution of cutting fluids. Finally, in view of the limitations of the cutting fluid and its circulating purification technique, the prospects of amino acid additive development, self-adapting jet parameter supply system, matching mechanism between processing conditions and cutting fluid are put forward, which provides the basis and support for the engineering application and development of cutting fluid and its circulating purification.

Chemokine Receptor CXCR-2 Initiates Atrial Fibrillation by Triggering Monocyte Mobilization in Mice.

Atrial fibrillation (AF) is frequently associated with increased inflammatory response characterized by infiltration of monocytes/macrophages. The chemokine receptor CXCR-2 is a critical regulator of monocyte mobilization in hypertension and cardiac remodeling, but it is not known whether CXCR-2 is involved in the development of hypertensive AF. AF was induced by infusion of Ang II (angiotensin II; 2000 ng/kg per minute) for 3 weeks in male C57BL/6 wild-type mice, CXCR-2 knockout mice, bone marrow-reconstituted chimeric mice, and mice treated with the CXCR-2 inhibitor SB225002. Microarray analysis revealed that 4 chemokine ligands of CXCR-2 were significantly upregulated in the atria during 3 weeks of Ang II infusion. CXCR-2 expression and the number of CXCR2+ immune cells markedly increased in Ang II-infused atria in a time-dependent manner. Moreover, Ang II-infused wild-type mice had increased blood pressure, AF inducibility, atrial diameter, fibrosis, infiltration of macrophages, and superoxide production compared with saline-treated wild-type mice, whereas these effects were significantly attenuated in CXCR-2 knockout mice and wild-type mice transplanted with CXCR-2-deficient bone marrow cells or treated with SB225002. Moreover, circulating blood CXCL-1 levels and CXCR2+ monocyte counts were higher and associated with AF in human patients (n=31) compared with sinus rhythm controls (n=31). In summary, this study identified a novel role for CXCR-2 in driving monocyte infiltration of the atria, which accelerates atrial remodeling and AF after hypertension. Blocking CXCR-2 activation may serve as a new therapeutic strategy for AF.

Alteration of the IL-33-sST2 pathway in hypertensive patients and a mouse model.

Inflammatory cells play an important role in the occurrence of hypertension. Recent studies have demonstrated that interleukin-33/suppression of tumorigenicity 2 (IL-33/ST2) signaling plays a critical role in the pathogenesis of several cardiovascular diseases. We aimed to evaluate the association of IL-33 and its receptor levels with the occurrence of hypertension in angiotensin II (Ang II)-infused mice using microarray analysis and validated our results in human specimens. Male wild-type mice were infused with Ang II (1500 ng/kg/min) for 1, 3 and 7 days. Patients with essential hypertension (EH) (n = 166) and healthy control subjects (n = 306) were enrolled. Levels of IL-33 and ST2 mRNAs in serum and peripheral blood mononuclear cells (PBMCs) were analyzed by Luminex assay or ELISA and qPCR analysis. We found that IL-33 expression was significantly increased in the aortas of mice receiving Ang II infusion compared with that of control mice. In contrast, the levels of IL-33 in serum and PBMCs were not significantly different between hypertensive patients and normal controls. However, the levels of soluble ST2 (sST2) in serum and PBMCs were markedly higher in hypertensive patients than in controls (P < 0.001 and P = 0.014, respectively). In addition, the ST2L level in PBMCs was also significantly decreased in hypertensive patients (P = 0.028). Further, logistic analysis showed that the odds ratios of having hypertension based on sST2 levels in serum and PBMCs were 9.714 and 2.244 (P = 0.013 and P = 0.024, respectively) compared with the control group. Above all, sST2 acted as a risk factor for the occurrence of hypertension and may be a promising novel predictive marker for EH.

The immunoproteasome catalytic ß5i subunit regulates cardiac hypertrophy by targeting the autophagy protein ATG5 for degradation.

Pathological cardiac hypertrophy eventually leads to heart failure without adequate treatment. The immunoproteasome is an inducible form of the proteasome that is intimately involved in inflammatory diseases. Here, we found that the expression and activity of immunoproteasome catalytic subunit ß5i were significantly up-regulated in angiotensin II (Ang II)-treated cardiomyocytes and in the hypertrophic hearts. Knockout of ß5i in cardiomyocytes and mice markedly attenuated the hypertrophic response, and this effect was aggravated by ß5i overexpression in cardiomyocytes and transgenic mice. Mechanistically, ß5i interacted with and promoted ATG5 degradation thereby leading to inhibition of autophagy and cardiac hypertrophy. Further, knockdown of ATG5 or inhibition of autophagy reversed the ß5i knockout-mediated reduction of cardiomyocyte hypertrophy induced by Ang II or pressure overload. Together, this study identifies a novel role for ß5i in the regulation of cardiac hypertrophy. The inhibition of ß5i activity may provide a new therapeutic approach for hypertrophic diseases.