Arginine vasopressin induces ferroptosis to promote heart failure via activation of the V1aR/CaN/NFATC3 pathway.

Arginine vasopressin (AVP) is a key contributor to heart failure (HF), but the underlying mechanisms remain unclear. In the present study, a mouse model of HF and human cardiomyocyte (HCM) cells treated with dDAVP are generated in vivo and in vitro, respectively. Hematoxylin and eosin (HE) staining is used to evaluate the morphological changes in the myocardial tissues. A colorimetric method is used to measure the iron concentration, Fe 2+ concentration and malondialdehyde (MDA) level. Western blot analysis is used to examine the protein levels of the V1a receptor (V1aR), calcineurin (CaN), nuclear factor of activated T cells isoform C3 (NFATC3), glutathione peroxidase 4 (GPX4) and acyl-CoA synthase long chain family member 4 (ACSL4). Immunoprecipitation (IP) and luciferase reporter assays are performed to determine the interaction between NFATC3 and ACSL4. Both in vivo and in vitro experiments reveal that the V1aR-CaN-NFATC3 signaling pathway and ferroptosis are upregulated in HFs, which are verified by the elevated protein levels of V1aR, CaN, NFATC3 and ACSL4; reduced GPX4 protein level; and enhanced Fe 2+ and MDA levels. We further find that inhibiting NFATC3 by suppressing the V1aR/CaN/NFATC3 pathway via V1aR/CaN inhibitors or sh-NFATC3 not only alleviates HF but also inhibits AVP-induced ferroptosis. Mechanistically, sh-NFATC3 significantly reverses the increase in AVP-induced ACSL4 protein level, Fe 2+ concentration, and MDA level by directly interacting with ACSL4. Our results demonstrate that AVP enhances ACSL4 expression by activating the V1aR/CaN/NFATC3 pathway to induce ferroptosis, thus contributing to HF. This study may lead to the proposal of a novel therapeutic strategy for HF.

Influence of enhanced external counterpulsation on endothelial function: a meta-analysis of randomized controlled trials.

OBJECTIVES: Enhanced external counterpulsation (EECP) is an effective and noninvasive treatment for patients with refractory angina and chronic heart failure. However, previous studies evaluating the influence of EECP on endothelial function showed inconsistent results. This systematic review and meta-analysis was conducted to evaluate the effects of EECP on endothelial function measured by brachial artery flow-mediated dilation (FMD). DESIGN: PubMed, Embase, Cochrane Library, CNKI, and Wanfang databases were searched for randomized controlled trials comparing the influence of EECP versus usual care on FMD in adult population. A random-effects model incorporating the potential influence of heterogeneity was used to pool the results. RESULTS: Nineteen studies with 1647 patients were included in the meta-analysis. Compared with usual care or conventional therapy, additional treatment with EECP for 3-7 weeks was associated with a significantly improved FMD (mean difference [MD]: 1.96%, 95% confidence interval [CI]: 1.57-2.36, p < 0.001, I2 = 52%). Subgroup analysis showed consistent results in patients with coronary artery disease and in patients with other diseases (p for subgroup difference = 0.21). Results of meta-regression analysis showed that the mean baseline FMD level was positively correlated with the influence of EECP on FMD (coefficient = 0.42, p < 0.001). Results of subgroup analysis suggested that the increment of FMD following EECP was larger in patients with baseline FMD ≥ 5% (MD: 2.69, 95% CI: 2.27-3.10, p < 0.001; I2 = 15%) compared to those with baseline FMD < 5% (MD: 1.49, 95% CI: 1.13-1.85, p < 0.001; I2 = 0%; p for subgroup difference < 0.001). CONCLUSIONS: EECP may be effective in improving endothelial function measured by FMD.

Clinical Efficacy of Fractional Flow Reserve-Guided Percutaneous Coronary Intervention in Coronary Heart Disease Patients with SYNTAX Score ≥33 and Euro Score ≥6: A Single-Center Retrospective Analysis.

OBJECTIVE: To observe clinical efficacy of fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) in coronary heart disease patients with SYNTAX scores (SS) ≥33 and Euro Scores (ES) ≥6 who are unsuitable for or have declined coronary artery bypass graft (CABG). METHODS: A total of 117 patients with SS ≥33 and Euro Score (ES) ≥6 who were unsuitable for and/or who had declined CABG between Jan 2021 and June 2022 were enrolled in this retrospective analysis. All patients accepted optimal medical therapy and some accepted an FFR-guided PCI procedure. Patients who only underwent optimal medical therapy were divided into the optimal medical therapy group (OMT group) and patients who simultaneously underwent FFR-guided PCI procedure were divided into the PCI group in this retrospective analysis. All patients accepted follow-up for at least 12 months after discharge. RESULTS: SS and ES in the two groups were not statistically different (p > 0.05). Patients with chronic total occlusion accounted for a greater proportion in the PCI subgroup (31.3%, 5/16) than in other subgroups. Eighteen (18.6%, 18/97) cases in the PCI group developed major adverse cardiac and cerebrovascular events (MACCEs). There were 12 (60%, 12/20) cases of MACCEs in the OMT group, which was statistically different from the PCI group (p < 0.05). CONCLUSIONS: Based on optimal medical therapy, FFR-guided PCI can still have clinical benefit to coronary artery disease patients with SS ≥33 who were not suitable for CABG.

Predictive value of long non-coding RNA intersectin 1-2 for occurrence and in-hospital mortality of severe acute pancreatitis.

BACKGROUND: This study aimed to investigate the predictive value of long non-coding RNA intersectin 1-2 (lnc-ITSN1-2) for severe acute pancreatitis (SAP) risk, and its correlation with disease severity and in-hospital mortality in SAP patients. METHODS: Plasma samples from 60 SAP, 60 moderate-severe acute pancreatitis (MSAP) and 60 mild acute pancreatitis (MAP) patients were collected within 24 hours, and plasma samples from 60 age and gender-matched healthy controls (HCs) were collected when enrollment. Lnc-ITSN1-2 was detected by reverse transcription-quantitative polymerase chain reaction. In AP patients, disease severity was evaluated and in-hospital deaths were recorded. RESULTS: Lnc-ITSN1-2 was increased in SAP patients compared with MSAP, MAP patients, and HCs, and it is well-discriminated SAP patients from MSAP patients (area under curve (AUC): 0.699, 95% confidence interval (CI): 0.605-0.792), MAP patients (AUC: 0.862, 95% CI: 0.798-0.926), and HCs (AUC: 0.958, 95% CI: 0.925-0.990). For disease severity, lnc-ITSN1-2 was positively correlated with Ranson's score, acute pathologic and chronic health evaluation (APACHE) II score, sequential organ failure assessment (SOFA) score, and C-reactive protein (CRP) in SAP patients, MSAP patients, and MAP patients; meanwhile, the correlation coefficients were highest in SAP patients. Furthermore, lnc-ITSN1-2 displayed a good predictive value for increased in-hospital mortality in SAP (AUC: 0.803, 95% CI: 0.673-0.933) and MSAP (AUC: 0.854, 95% CI: 0.752-0.956) patients, which was similar with several common prognostic factors (including Ranson's score, APACHE II score, SOFA score, and CRP). CONCLUSION: Lnc-ITSN1-2 might be a potential biomarker for discrimination of SAP to improve the prognosis of SAP patients.

Hydrochlorothiazide modulates ischemic heart failure-induced cardiac remodeling via inhibiting angiotensin II type 1 receptor pathway in rats.

AIMS: Our previous study indicates that hydrochlorothiazide inhibits transforming growth factor (TGF)-ß/Smad signaling pathway, improves cardiac function and reduces fibrosis. We determined whether these effects were common among the diuretics and whether angiotensin II receptor type 1 (AT1) signaling pathway played a role in these effects. METHODS: Heart failure was produced by ligating the left anterior descending coronary artery in adult male Sprague Dawley rats. Two weeks after the ligation, 70 rats were randomly divided into five groups: sham-operated group, control group, valsartan group (80 mg/kg/d), hydrochlorothiazide group (12.5 mg/kg/d) and furosemide group (20 mg/kg/d). In addition, neonatal rat ventricular fibroblasts were treated with angiotensin II. RESULTS: After eight-week drug treatment, hydrochlorothiazide group and valsartan group but not furosemide group had improved cardiac function (ejection fraction was 49.4±2.1%, 49.5±1.8% and 39.9±1.9%, respectively, compared with 40.1±2.2% in control group), reduced cardiac interstitial fibrosis and collagen volume fraction (9.7±1.2%, 10.0±1.3% and 14.1±0.8%, respectively, compared with 15.9±1.1% in control group), and decreased expression of AT1, TGF-ß and Smad2 in the cardiac tissues. In addition, hydrochlorothiazide reduced plasma angiotensin II and aldosterone levels. Furthermore, hydrochlorothiazide inhibited angiotensin II-induced TGF-ß1 and Smad2 protein expression in the neonatal rat ventricular fibroblasts. CONCLUSIONS: Our study indicates that the cardiac function and remodeling improvement after ischemic heart failure may not be common among the diuretics. Hydrochlorothiazide may reduce the left ventricular wall stress and angiotensin II signaling pathway to provide these beneficial effects.

The secretion patterns and roles of cardiac and circulating arginine vasopressin during the development of heart failure.

OBJECTIVE: The aim of this study is to investigate local cardiac and circulating AVP secretion during heart failure and to determine whether AVP mediates ventricular remodeling. METHODS: We assessed cardiac function and AVP levels of post-myocardial infarction (MI) heart-failure rats 3 weeks (n = 10), 4 weeks (n = 10), 6 weeks (n = 10), 9 weeks (n = 15) after the proximal left anterior descending coronary artery (LAD) ligation. Ten sham-operated rats were used as the control group. In vitro, cardiac microvascular endothelial cells (CMECs) were initiated from isolated Wistar rat hearts and subjected to Ang II to induce AVP expression and secretion. Besides, the effects of AVP stimulation on CMECs and cardiac fibroblasts (CFs) were studied using methylthiazol tetrazolium assay, Western blotting and real-time PCR. RESULTS: With cardiac dysfunction, plasma and local cardiac AVP, aldosterone levels increased over time, peaking at 9 weeks post-MI. AVP levels were negatively correlated with serum Na(+) and LVEF but positively correlated with LVEDD and myocardial hydroxyproline. In CMECs treated with Ang II, AVP mRNA and protein expression increased. In addition, AVP promoted CFs proliferation and up-regulated the expression of endothelin-1 and connective tissue growth factor. CONCLUSION: CMECs are the cellular sources of elevated local heart AVP stimulated with Ang II/AT1. An intrinsic cardiac AVP system exists. Local cardiac and circulating AVP secretion were enhanced by deteriorating cardiac function. AVP may promote ventricular remodeling. Thus, AVP could be an important mediator of myocardial fibrosis in late-stage heart failure.

Changes in cell autophagy and apoptosis during age-related left ventricular remodeling in mice and their potential mechanisms.

Cardiac structures and functions change with advanced age, but the underlying mechanisms are not well understood. Autophagy and apoptosis play important roles in the process of cardiac remodeling. This study was designed to explore changes in cell autophagy and apoptosis during age-related left ventricular remodeling and to determine whether the mitogen-activated protein kinase (MAPK) pathway is an underlying mechanism. Eight 5-month-old (adult group) and eight 24-month-old male C57bl/6 mice (aged group) were studied. The heart mass index, left ventricular mass index and hydroxyproline content of both groups were compared. Western Blotting was used to quantitate the protein expression of microtubule-associated protein 1 light chain 3 (LC3), Beclin-1, caspase-3, B-cell leukemia-2 (Bcl-2) and MAPKs in the left ventricles of adult and aged mice. Our results showed that the heart mass index, left ventricular mass index and hydroxyproline content in the left ventricles of the aged mice were increased significantly compared with the adult mice, indicating that left ventricular remodeling occurs with aging. The expression of LC3 and Beclin-1 in the left ventricles of aged mice were decreased significantly compared to adult mice. Meanwhile, the level of myocardial caspase-3 in adult mice remained the same in aged mice, and the level of myocardial Bcl-2 increased significantly in aged mice. There were no differences in the expression level of myocardial extracellular signal-regulated kinase 1/2 (ERK1/2), activated/phospho-ERK1/2, c-Jun N-terminal kinase 1/2 (JNK1/2) and p38 between aged and adult mice. However, the expression of myocardial activated/phospho-JNK1/2 increased significantly in aged mice, while activated/phospho-p38 decreased significantly. These findings indicate that autophagy decreases without a concurrent change in apoptosis during age-related left ventricular remodeling in mice. The MAPK pathway may be involved in the regulation of age-related left ventricular remodeling by modulating autophagy.