IL-1 signaling pathway, an important target for inflammation surrounding in myocardial infarction.

Acute myocardial infarction is an important cardiovascular disease worldwide. Although the mortality rate of myocardial infarction (MI) has improved dramatically in recent years due to timely treatment, adverse remodeling of the left ventricle continues to affect cardiac function. Various immune cells are involved in this process to induce inflammation and amplification. The infiltration of inflammatory cells in the infarcted myocardium is induced by various cytokines and chemokines, and the recruitment of leukocytes further amplifies the inflammatory response. As an increasing number of clinical anti-inflammatory therapies have achieved significant success in recent years, treating myocardial infarction by targeting inflammation may become a novel therapeutic option. In particular, successful clinical trials of canakinumab have demonstrated the important role of the inflammatory factor interleukin-1 (IL-1) in atherosclerosis. Targeted IL-1 therapy may decrease inflammation levels and improve cardiac function in patients after myocardial infarction. This article reviews the complex series of responses after myocardial infarction, including the involvement of inflammatory cells and the role of cytokines and chemokines, focusing on the progression of the IL-1 family in myocardial infarction as well as the performance of current targeted therapy drugs in experiments.

Vaccine Targeting Alpha 1D-Adrenergic Receptor Improved Metabolic Syndrome in Mice.

PURPOSE: Metabolic syndrome (MetS) is a complex chronic disease that includes obesity and hypertension, with rising evidence demonstrating that sympathetic nervous system (SNS) activation plays a key role. Our team designed a therapeutic vaccine called ADRQß-004 targeting the α1D-adrenergic receptor (α1D-AR). This study was performed to investigate whether the ADRQß-004 vaccine improves MetS by modulating SNS activity. METHODS: C57BL/6N mice were fed a high-fat diet (HFD) and Nω-nitro-L-arginine methyl ester (L-NAME) combination diet for 18 weeks to elicit MetS. The MetS mice were subcutaneously immunized with the ADRQß-004 vaccine four times to evaluate the therapeutic efficacy in obesity and hypertension and other associated abnormalities related to MetS by conducting echocardiographic, histological, and biochemical analyses. RESULTS: The ADRQß-004 vaccine induced strong antibody production and maintained a high anti-ADR-004 antibody titer in MetS mice. The ADRQß-004 vaccine improved obesity (P < 0.001) and decreased systolic blood pressure (P < 0.001). Improvements in dysregulated glucose homeostasis and dyslipidemia resulting from the ADRQß-004 vaccine were also confirmed. Furthermore, the ADRQß-004 vaccine attenuated cardiovascular functional (P = 0.015) and structural changes (P < 0.001), decreased fat accumulation (P = 0.012) and inflammation (P = 0.050) in the epididymal white adipose tissue, and alleviated hepatic steatosis (P = 0.043) involved in MetS. Moreover, the ADRQß-004 vaccine improved systematic and visceral organs SNS activities in the MetS. CONCLUSION: This study demonstrated for the first time that the ADRQß-004 vaccine targeting α1D-AR improved obesity, hypertension, dyslipidemia, and dysglycemia, and further reduced end-organ damage, which may provide new motivation for MetS research.

Combined vaccines against angiotensin II receptor type 1 and alpha 1D-adrenergic receptor for hypertension.

PURPOSE: Compared with monotherapy, combination therapy with multiple antihypertensive drugs has demonstrated superior efficacy in the management of hypertension. The aim of this study was to explore the efficacy of multitarget combined vaccines in achieving simultaneous antihypertensive and target organ protection effects. METHODS: Our team has developed ATRQß-001 and ADRQß-004 vaccines targeting Ang II type 1 receptor (AT1R) and α1D-adrenergic receptor (α1D-AR), respectively. In NG-nitroarginine methyl ester ( l -NAME) + abilities spontaneously hypertensive rats (SHRs) model, SHRs were simultaneously inoculated with ATRQß-001 and ADRQß-004 vaccines. Histological and biochemical analyses were performed to evaluate the antihypertensive effects and target organ protection of the ATRQß-001 and ADRQß-004 combined vaccines in comparison with those of the single vaccine. RESULTS: Both ATRQß-001 and ADRQß-004 vaccines induced robust antibody production, resulting in persistent high antibody titers in rats. Notably, the combined administration of both vaccines significantly decreased SBP in SHRs compared with treatment with a single vaccine, both before and after l -NAME administration. Furthermore, the combined vaccine regimen demonstrated superior efficacy in protecting against vascular remodeling, myocardial hypertrophy and fibrosis, and kidney injury in SHRs. Mechanistically, the combined vaccines exhibited significantly downregulated the expression of angiotensin II type 1 receptor (AT1R) and α1D-adrenergic receptor (α1D-AR). Importantly, no apparent immune-related adverse effects were observed in animals immunized with the combined vaccines. CONCLUSION: Preliminary findings from this investigation suggest that co-administration of the novel ATRQß-001 and ADRQß-004 vaccines holds potential as a groundbreaking therapeutic strategy for managing hypertension.

The novel vaccines targeting interleukin-1 receptor type I.

OBJECTIVE: There is mounting evidence indicating that atherosclerosis represents a persistent inflammatory process, characterized by the presence of inflammation at various stages of the disease. Interleukin-1 (IL-1) precisely triggers inflammatory signaling pathways by binding to interleukin-1 receptor type I (IL-1R1). Inhibition of this signaling pathway contributes to the prevention of atherosclerosis and myocardial infarction. The objective of this research is to develop therapeutic vaccines targeting IL-1R1 as a preventive measure against atherosclerosis and myocardial infarction. METHODS: ILRQß-007 and ILRQß-008 vaccines were screened, prepared and then used to immunize high-fat-diet fed ApoE-/- mice and C57BL/6J mice following myocardial infarction. Progression of atherosclerosis in ApoE-/- mice was assessed primarily by oil-red staining of the entire aorta and aortic root, as well as by detecting the extent of macrophage infiltration. The post-infarction cardiac function in C57BL/6J mice were evaluated using cardiac ultrasound and histological staining. RESULTS: ILRQß-007 and ILRQß-008 vaccines stimulated animals to produce high titers of antibodies that effectively inhibited the binding of interleukin-1ß and interleukin-1α to IL-1R1. Both vaccines effectively reduced atherosclerotic plaque area, promoted plaque stabilization, decreased macrophage infiltration in plaques and influenced macrophage polarization, as well as decreasing levels of inflammatory factors in the aorta, serum, and ependymal fat in ApoE-/- mice. Furthermore, these vaccines dramatically improved cardiac function and macrophage infiltration in C57BL/6J mice following myocardial infarction. Notably, no significant immune-mediated damage was observed in immunized animals. CONCLUSION: The vaccines targeting the IL-1R1 would be a novel and promising treatment for the atherosclerosis and myocardial infarction.

G protein-coupled estrogen receptor: a promising therapeutic target for aldosterone-induced hypertension.

Aldosterone is one of the most essential hormones synthesized by the adrenal gland because it regulates water and electrolyte balance. G protein-coupled estrogen receptor (GPER) is a newly discovered aldosterone receptor, which is proposed to mediate the non-genomic pathways of aldosterone while the hormone simultaneously interacts with mineralocorticoid receptor. In contrast to its cardio-protective role in postmenopausal women via its interaction with estrogen, GPER seems to trigger vasoconstriction effects and can further induce water and sodium retention in the presence of aldosterone, indicating two entirely different binding sites and effects for estrogen and aldosterone. Accumulating evidence also points to a role of aldosterone in mediating hypertension and its risk factors via the interaction with GPER. Therefore, with this review, we aimed to summarize the research on these interactions to help (1) elucidate the role of GPER activated by aldosterone in the blood vessels, heart, and kidney; (2) compare the non-genomic actions between aldosterone and estrogen mediated by GPER; and (3) address the potential of GPER as a new promising therapeutic target for aldosterone-induced hypertension.

Hypocapnia is an independent predictor of in-hospital mortality in acute heart failure.

AIMS: Acute heart failure (AHF) poses a major threat to hospitalized patients for its high mortality rate and serious complications. The aim of this study is to determine whether hypocapnia [defined as the partial pressure of arterial carbon dioxide (PaCO2 ) below 35 mmHg] on admission could be associated with in-hospital all-cause mortality in AHF. METHODS AND RESULTS: A total of 676 patients treated in the coronary care unit for AHF were retrospectively analysed, and the study endpoint was in-hospital all-cause mortality. The 1:1 propensity score matching (PSM) analysis, Kaplan-Meier curve, and Cox regression model were used to explore the association between hypocapnia and in-hospital all-cause mortality in AHF. Receiver operating characteristic (ROC) curve and Delong's test were used to assess the performance of hypocapnia in predicting in-hospital all-cause mortality in AHF. The study cohort included 464 (68.6%) males and 212 (31.4%) females, and the median age was 66 years (interquartile range 56-74 years). Ninety-eight (14.5%) patients died during hospitalization and presented more hypocapnia than survivors (76.5% vs. 45.5%, P < 0.001). A 1:1 PSM was performed between hypocapnic and non-hypocapnic patients, with 264 individuals in each of the two groups after matching. Compared with non-hypocapnic patients, in-hospital mortality was significantly higher in hypocapnic patients both before (22.2% vs. 6.8%, P < 0.001) and after (20.8% vs. 8.7%, P < 0.001) PSM. Kaplan-Meier curve showed a significantly higher probability of in-hospital death in patients with hypocapnia before and after PSM (both P < 0.001 for the log-rank test). Multivariate Cox regression analysis showed that hypocapnia was an independent predictor of AHF mortality both before [hazard ratio (HR) 2.22; 95% confidence interval (CI) 1.23-3.98; P = 0.008] and after (HR 2.19; 95% CI 1.18-4.07; P = 0.013) PSM. Delong's test showed that the area under the ROC curve was improved after adding hypocapnia into the model (0.872, 95% CI 0.839-0.901 vs. 0.855, 95% CI 0.820-0.886, P = 0.028). PaCO2 was correlated with the estimated glomerular filtration rate (r = 0.20, P = 0.001), left ventricular ejection fraction (r = 0.13, P < 0.001), B-type natriuretic peptide (r = -0.28, P < 0.001), and lactate (r = -0.15, P < 0.001). Kaplan-Meier curve of PaCO2 tertiles and multivariate Cox regression analysis showed that the lowest PaCO2 tertile was associated with increased risk of in-hospital mortality in AHF (all P < 0.05). CONCLUSIONS: Hypocapnia is an independent predictor of in-hospital mortality for AHF.

A novel vaccine targeting ß1-adrenergic receptor.

Beta-blockers are widely used in the treatment of hypertension, heart failure and ischemic heart disease. However, unstandardized medication results in diverse clinical outcomes in patients. The main causes are unattained optimal doses, insufficient follow-up and patients' poor adherence. To improve the medication inadequacy, our team developed a novel therapeutic vaccine targeting ß1-adrenergic receptor (ß1-AR). The ß1-AR vaccine named ABRQß-006 was prepared by chemical conjugation of a screened ß1-AR peptide with Qß virus like particle (VLP). The antihypertensive, anti-remodeling and cardio-protective effects of ß1-AR vaccine were evaluated in different animal models. The ABRQß-006 vaccine was immunogenic that induced high titers of antibodies against ß1-AR epitope peptide. In the NG-nitro-L-arginine methyl ester (L-NAME) + Sprague Dawley (SD) hypertension model, ABRQß-006 lowered systolic blood pressure about 10 mmHg and attenuated vascular remodeling, myocardial hypertrophy and perivascular fibrosis. In the pressure-overload transverse aortic constriction (TAC) model, ABRQß-006 significantly improved cardiac function, decreased myocardial hypertrophy, perivascular fibrosis and vascular remodeling. In the myocardial infarction (MI) model, ABRQß-006 effectively improved cardiac remodeling, reduced cardiac fibrosis and inflammatory infiltration, which was superior to metoprolol. Moreover, no significant immune-mediated damage was observed in immunized animals. The ABRQß-006 vaccine targeting ß1-AR showed the effects on hypertension and heart rate control, myocardial remodeling inhibition and cardiac function protection. These effects could be differentiated in different types of diseases with diverse pathogenesis. ABRQß-006 could be a novel and promising method for the treatment of hypertension and heart failure with different etiologies.

Targeting Cancer Cell Ferroptosis to Reverse Immune Checkpoint Inhibitor Therapy Resistance.

In recent years, cancer therapies using immune checkpoint inhibitors (ICIs) have achieved meaningful success, with patients with advanced tumors presenting longer survival times and better quality of life. However, several patients still do not exhibit good clinical outcomes for ICI therapy due to low sensitivity. To solve this, researchers have focused on identifying the cellular and molecular mechanisms underlying resistance to ICI therapy. ICI therapy induces apoptosis, which is the most frequent regulated cell death (RCD) but lacks immunogenicity and is regarded as an "immune silent" cell death. Ferroptosis, a unique type of non-apoptotic-RCD, has been preliminarily identified as an immunogenic cell death (ICD), stimulating tumor-antigen-specific immune responses and augmenting anti-tumor immune effects. However, ferroptosis has rarely been used in clinical practice. Present evidence strongly supports that the interferon-γ signaling pathway is at the crossroads of ICI therapy and ferroptosis. TYRO3, a receptor tyrosine kinase, is highly expressed in tumors and can induce anti-programmed cell death (PD)-ligand 1/PD-1 therapy resistance by limiting tumoral ferroptosis. Therefore, in this review, we summarize the clinical practice and effects of ICI therapy in various cancers. We also provide an overview of ferroptosis and report the molecular connections between cancer cell ferroptosis and ICI therapy, and discuss the possibility to reverse ICI therapy resistance by inducing cancer cell ferroptosis.