Epidermal Growth Factor-Like Repeats and Discoidin I-Like Domains 3 Deficiency Attenuates Dilated Cardiomyopathy by Inhibiting Ubiquitin Specific Peptidase 10 Dependent Smad4 Deubiquitination.

BACKGROUND: Dilated cardiomyopathy (DCM) is the leading cause of heart failure with a poor prognosis. Recent studies suggest that endothelial to mesenchymal transition (EndMT) may be involved in the pathogenesis and cardiac remodeling during DCM development. EDIL3 (epidermal growth factor-like repeats and discoidin I-like domains 3) is an extracellular matrix glycoprotein that has been reported to promote EndMT in various diseases. However, the roles of EDIL3 in DCM still remain unclear. METHODS AND RESULTS: A mouse model of DCM and human umbilical vein endothelial cells were used to explore the roles and mechanisms of EDIL3 in DCM. The results indicated that EndMT and EDIL3 were activated in DCM mice. EDIL3 deficiency attenuated cardiac dysfunction and remodeling in DCM mice. EDIL3 knockdown alleviated EndMT by inhibiting USP10 (ubiquitin specific peptidase 10) dependent Smad4 deubiquitination in vivo and in vitro. Recombinant human EDIL3 promoted EndMT via reinforcing deubiquitination of Smad4 in human umbilical vein endothelial cells treated with IL-1ß (interleukin 1ß) and TGF-ß (transforming growth factor beta). Inhibiting USP10 abolished EndMT exacerbated by EDIL3. In addition, recombinant EDIL3 also aggravates doxorubicin-induced EndMT by promoting Smad4 deubiquitination in HUVECs. CONCLUSIONS: Taken together, these results indicate that EDIL3 deficiency attenuated EndMT by inhibiting USP10 dependent Smad4 deubiquitination in DCM mice.

Maresin-1 ameliorates hypertensive vascular remodeling through its receptor LGR6.

Hypertensive vascular remodeling is defined as the changes in vascular function and structure induced by persistent hypertension. Maresin-1 (MaR1), one of metabolites from Omega-3 fatty acids, has been reported to promote inflammation resolution in several inflammatory diseases. This study aims to investigate the effect of MaR1 on hypertensive vascular remodeling. Here, we found serum MaR1 levels were reduced in hypertensive patients and was negatively correlated with systolic blood pressure (SBP). The treatment of MaR1 reduced the elevation of blood pressure and alleviated vascular remodeling in the angiotensin II (AngII)-infused mouse model. In addition, MaR1-treated vascular smooth muscle cells (VSMCs) exhibited reduced excessive proliferation, migration, and phenotype switching, as well as impaired pyroptosis. However, the knockout of the receptor of MaR1, leucine-rich repeat-containing G protein-coupled receptor 6 (LGR6), was seen to aggravate pathological vascular remodeling, which could not be reversed by additional MaR1 treatment. The mechanisms by which MaR1 regulates vascular remodeling through LGR6 involves the Ca2+/calmodulin-dependent protein kinase II/nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling pathway. Overall, supplementing MaR1 may be a novel therapeutic strategy for the prevention and treatment of hypertension.

Kielin/chordin-like protein deficiency aggravates pressure overload-induced cardiac dysfunction and remodeling via P53/P21/CCNB1 signaling in mice.

Targeting cardiac remodeling is regarded as a key therapeutic strategy for heart failure. Kielin/chordin-like protein (KCP) is a secretory protein with 18 cysteine-rich domains and associated with kidney and liver fibrosis. However, the relationship between KCP and cardiac remodeling remains unclear. Here, we aimed to investigate the role of KCP in cardiac remodeling induced by pressure overload and explore its potential mechanisms. Left ventricular (LV) KCP expression was measured with real-time quantitative PCR, western blotting, and immunofluorescence staining in pressure overload-induced cardiac remodeling in mice. Cardiac function and remodeling were evaluated in wide-type (WT) mice and KCP knockout (KO) mice by echocardiography, which were further confirmed by histological analysis with hematoxylin and eosin and Masson staining. RNA sequence was performed with LV tissue from WT and KO mice to identify differentially expressed genes and related signaling pathways. Primary cardiac fibroblasts (CFs) were used to validate the regulatory role and potential mechanisms of KCP during fibrosis. KCP was down-regulated in the progression of cardiac remodeling induced by pressure overload, and was mainly expressed in fibroblasts. KCP deficiency significantly aggravated pressure overload-induced cardiac dysfunction and remodeling. RNA sequence revealed that the role of KCP deficiency in cardiac remodeling was associated with cell division, cell cycle, and P53 signaling pathway, while cyclin B1 (CCNB1) was the most significantly up-regulated gene. Further investigation in vivo and in vitro suggested that KCP deficiency promoted the proliferation of CFs via P53/P21/CCNB1 pathway. Taken together, these results suggested that KCP deficiency aggravates cardiac dysfunction and remodeling induced by pressure overload via P53/P21/CCNB1 signaling in mice.

Resolvin D1 attenuates Ang II-induced hypertension in mice by inhibiting the proliferation, migration and phenotypic transformation of vascular smooth muscle cells by blocking the RhoA/mitogen-activated protein kinase pathway.

The proliferation, migration and phenotypic transformation of vascular smooth muscle cells contribute to vascular remodeling and hypertension. Resolvin D1 (RvD1) is a specialized pro-resolving lipid mediator that has been shown to have anti-inflammatory effects and can protect against different cardiovascular diseases. However, the role and mechanism of RvD1 in hypertension are not clear. The current study investigated the role of RvD1 in Ang II-induced hypertensive mice and Ang II-stimulated rat vascular smooth muscle cells. The results showed that RvD1 treatment significantly attenuated hypertension and vascular remodeling, as indicated by decreases in blood pressure, aortic media thickness and collagen deposition. In addition, RvD1 inhibited the proliferation, migration and phenotypic transformation of vascular smooth muscle cells (VSMCs) in vivo and in vitro . Notably, the protective effects of RvD1 were mediated by the Ras homolog gene family member A (RhoA)/mitogen-activated protein kinase (MAPK) signaling pathway. In conclusion, our findings demonstrated the potential benefits of RvD1 as a promising therapeutic agent in the treatment of vascular remodeling and hypertension.

DEL-1 deficiency aggravates pressure overload-induced heart failure by promoting neutrophil infiltration and neutrophil extracellular traps formation.

Recent studies have shown that neutrophils play an important role in the development and progression of heart failure. Developmental endothelial locus-1 (DEL-1) is an anti-inflammatory glycoprotein that has been found to have protective effects in various cardiovascular diseases. However, the role of DEL-1 in chronic heart failure is not well understood. In a mouse model of pressure overload-induced non-ischemic cardiac failure, we found that neutrophil infiltration in the heart increased and DEL-1 levels decreased in the early stages of heart failure. DEL-1 deficiency worsened pressure overload-induced cardiac dysfunction and remodeling in mice. Mechanistically, DEL-1 deficiency promotes neutrophil infiltration and the formation of neutrophil extracellular traps (NETs) through the regulation of P38 signaling. In vitro experiments showed that DEL-1 can inhibit P38 signaling and NETs formation in mouse neutrophils in a MAC-1-dependent manner. Depleting neutrophils, inhibiting NETs formation, and inhibiting P38 signaling all reduced the exacerbation of heart failure caused by DEL-1 deletion. Overall, our findings suggest that DEL-1 deficiency worsens pressure overload-induced heart failure by promoting neutrophil infiltration and NETs formation.

The Anti-Inflammatory Mediator 17(R)-Resolvin D1 Attenuates Pressure Overload-Induced Cardiac Hypertrophy and Fibrosis.

Background: Increased inflammation contributes to pressure overload-induced myocardial remodeling. 17(R)-Resolvin D1 (17(R)-RvD1), a potent lipid mediator derived from docosahexaenoic acid, possesses anti-inflammatory and pro-resolving properties. However, the association between 17(R)-RvD1 and pressure overload-induced cardiac hypertrophy remains unclear. Methods: Transverse aortic constriction (TAC) surgery was performed to establish a cardiac hypertrophy model. C57BL/6J mice were randomly assigned to the Sham, TAC and TAC+17(R)-RvD1 groups. 17(R)-RvD1 was injected (2 µg/kg, i.p.) before TAC surgery and once every other day after surgery for 4 weeks. The same volume of saline was injected into the mice in both Sham group and TAC group. Then, cardiac function was evaluated and heart tissues were collected for biological analysis. Results: 17(R)-RvD1 treatment attenuated TAC-induced increase in left ventricular diameter and decrease in left ventricular contractility, mitigated increased cardiomyocyte cross-sectional area, and downregulated the expression of hypertrophic genes. Besides, 17(R)-RvD1 attenuated myocardial fibrosis, as indicated by the decreased LV collagen volume and expression of fibrotic genes. In addition, 17(R)-RvD1 ameliorated the inflammatory response in cardiac tissue, as illustrated by the decreased infiltration of CD68+ macrophages and reduced production of pro-inflammatory cytokines, including TNF-α, IL-1ß, and IL-6. 17(R)-RvD1 treatment significantly suppressed the activation of NLRP3 inflammasome after TAC surgery, which might be responsible for the attenuation of inflammation in cardiac tissue. Conclusion: 17(R)-RvD1 attenuated pressure overload-induced cardiac hypertrophy and fibrosis, and the possible mechanism may be associated with the inhibition of NLRP3 inflammasome. 17(R)-RvD1 may serve as a potential drug for the treatment of cardiac hypertrophy.

Resolvin E1/ChemR23 Protects Against Hypertension and Vascular Remodeling in Angiotensin II-Induced Hypertensive Mice.

BACKGROUND: Inflammation plays a critical role in the development of hypertension and vascular remodeling. Resolvin E1 (RvE1), as one of the specialized proresolving lipid mediators, promotes inflammation resolution by binding with a G protein-coupled receptor, ChemR23 (chemerin receptor 23). However, whether RvE1/ChemR23 regulates hypertension and vascular remodeling is unknown. METHODS: Hypertension in mice was induced by Ang II (angiotensin II) infusion (750 ng/kg per minute), and RvE1 (2 µg/kg per day) was administered through intraperitoneal injection. Loss of ChemR23 was achieved by mice receiving intravenous injection of adeno-associated virus 9-encoding shRNA against ChemR23. RESULTS: Aortic ChemR23 expression was increased in Ang II-induced hypertensive mice and that ChemR23 was mainly expressed on vascular smooth muscle cells (VSMCs). RvE1 lowered blood pressure, reduced aortic media thickness, attenuated aortic fibrosis, and mitigated VSMC phenotypic transformation and proliferation in hypertensive mice, which were all reversed by the knockdown of ChemR23. Moreover, RvE1 reduced the aortic infiltration of macrophages and T cells, which was also reversed by ChemR23 knockdown. RvE1 inhibited Ccl5 expression in VSMCs via the AMPKα (AMP-activated protein kinase α)/Nrf2 (nuclear factor E2-related factor 2)/canonical NF-κB (nuclear factor κB) pathway, thereby reducing the infiltration of macrophages and T cells. The AMPKα/Nrf2 pathway also mediated the effects of RvE1 on VSMC phenotypic transformation and proliferation. In patients with hypertension, the serum levels of RvE1 and other eicosapentaenoic acid-derived metabolites were significantly decreased. CONCLUSIONS: RvE1/ChemR23 ameliorated hypertension and vascular remodeling by activating AMPKα/Nrf2 signaling, which mediated immune cell infiltration by inhibiting the canonical NF-κB/Ccl5 pathway, and regulated VSMC proliferation and phenotypic transformation. RvE1/ChemR23 may be a potential therapeutic target for hypertension.

Macrophage neogenin deficiency exacerbates myocardial remodeling and inflammation after acute myocardial infarction through JAK1-STAT1 signaling.

Immune response plays a crucial role in post-myocardial infarction (MI) myocardial remodeling. Neogenin (Neo1), a multifunctional transmembrane receptor, plays a critical role in the immune response; however, whether Neo1 participates in pathological myocardial remodeling after MI is unclear. Our study found that Neo1 expression changed significantly after MI in vivo and after LPS + IFN-γ stimulation in bone marrow-derived macrophages (BMDMs) in vitro. Neo1 functional deficiency (using a neutralizing antibody) and macrophage-specific Neo1 deficiency (induced by Neo1flox/flox;Cx3cr1cre mice) increased infarction size, enhanced cardiac fibrosis and cardiomyocyte apoptosis, and exacerbated left ventricular dysfunction post-MI in mice. Mechanistically, Neo1 deficiency promoted macrophage infiltration into the ischemic myocardium and transformation to a proinflammatory phenotype, subsequently exacerbating the inflammatory response and impairing inflammation resolution post-MI. Neo1 deficiency regulated macrophage phenotype and function, possibly through the JAK1-STAT1 pathway, as confirmed in BMDMs in vitro. Blocking the JAK1-STAT1 pathway with fludarabine phosphate abolished the impact of Neo1 on macrophage phenotype and function, inflammatory response, inflammation resolution, cardiomyocyte apoptosis, cardiac fibrosis, infarction size and cardiac function. In conclusion, Neo1 deficiency aggravates inflammation and left ventricular remodeling post-MI by modulating macrophage phenotypes and functions via the JAK1-STAT1 signaling pathway. These findings highlight the anti-inflammatory potential of Neo1, offering new perspectives for therapeutic targets in MI treatment. Neo1 deficiency aggravated inflammation and left ventricular remodeling after MI by modulating macrophage phenotypes and functions via the JAK1-STAT1 signaling pathway.

IL-30 protects against sepsis-induced myocardial dysfunction by inhibiting pro-inflammatory macrophage polarization and pyroptosis.

Cardiac dysfunction is a well-recognized complication of sepsis and seriously affects the prognosis of sepsis patients. IL-30 has been reported to exert anti-inflammatory effects in various diseases. However, the role of IL-30 in sepsis-induced myocardial dysfunction (SIMD) remains unclear. Here, we explored the protective role of IL-30 in cecum ligation and puncture (CLP)-induced SIMD mice. IL-30 expression increased in the cardiac tissues of septic mice and was mainly derived from macrophages. IL-30 deletion or neutralization aggravated sepsis-induced cardiac dysfunction and injury, whereas recombinant IL-30 treatment significantly ameliorated it. Mechanistically, IL-30 deficiency exerts pro-inflammatory effects by promoting Ly6Chigh macrophage polarization and pyroptosis. Inhibiting NLRP3 with MCC950 significantly reversed cardiac dysfunction, macrophage polarization and pyroptosis aggravated by IL-30 deficiency. Recombinant IL-30 inhibited pro-inflammatory macrophage polarization and pyroptosis in vivo and vitro. Taken together, these results suggest that IL-30 protects against SIMD by inhibiting pro-inflammatory macrophage polarization and pyroptosis.

TRPA1 deficiency attenuates cardiac fibrosis via regulating GRK5/NFAT signaling in diabetic rats.

BACKGROUND: Transient receptor potential ankyrin 1 (TRPA1) has been linked to the development of various cardiovascular diseases, but its role in diabetic cardiomyopathy is not well understood. This study aimed to investigate the protective effects of TRPA1 deficiency on diabetic cardiomyopathy in rats with streptozotocin-induced diabetes and in neonatal rat cardiac fibroblasts (CFs) exposed to high glucose (HG). METHODS: Cardiac TRPA1 expression levels were measured in diabetic rats. Cardiac function, remodeling, and fibrosis were analyzed in Sprague-Dawley (SD) rats and TRPA1-deficient rats with diabetic cardiomyopathy. In vitro, fibrosis was measured in CFs exposed to HG. Additionally, 1,8-cineole, a natural inhibitor of TRPA1, was used to treat SD rats with diabetic cardiomyopathy. RESULTS: TRPA1 expression was increased in the heart tissue of diabetic rats and in CFs treated with HG. TRPA1 deficiency significantly improved cardiac function in diabetic rats, as evidenced by improved echocardiography and reduced cardiac hypertrophy and fibrosis. In vitro, TRPA1 deficiency suppressed the transformation of HG-induced CFs into myofibroblasts. The cardioprotective effect of TRPA1 deficiency was found to inhibit cardiac fibrosis by regulating GRK5/NFAT signaling. Furthermore, inhibition of GRK5/NFAT signaling abolished the promotion of CF transformation into myofibroblasts by TRPA1 activation. Inhibition of TRPA1 activation by 1,8-cineole reduced cardiac dysfunction and remodeling in diabetic rats by regulating GRK5/NFAT signaling. CONCLUSIONS: TRPA1 deficiency reduced cardiac fibrosis in diabetic rats and inhibited HG-induced CF activation in vitro by regulating GRK5/NFAT signaling. The TRPA1 inhibitor 1,8-cineole may serve as a novel therapeutic agent for the treatment of diabetic cardiomyopathy.

Microglia-Mediated Neuroimmune Response Regulates Cardiac Remodeling After Myocardial Infarction.

Background Sympathetic hyperactivity contributes to pathological remodeling after myocardial infarction (MI). However, the mechanisms underlying the increase in sympathetic activity remain unknown. Microglia are the predominant immune cells in the central nervous system and can regulate sympathetic neuron activity through neuroimmune response in the hypothalamic paraventricular nucleus. The present study aimed to investigate whether microglia-mediated neuroimmune response can regulate sympathetic activity and cardiac remodeling after MI. Methods and Results PLX3397 (pexidartinib) was used to deplete central microglia via intragastric injection or intracerebroventricular injection. After that, MI was induced by ligation of the left anterior descending coronary artery. Our study showed that MI resulted in the activation of microglia in the paraventricular nucleus. Microglia depletion, which was induced by PLX3397 treatment via intragastric injection or intracerebroventricular injection, improved cardiac function, reduced infarction size, and attenuated cardiomyocyte apoptosis, fibrosis, pathological electrical remodeling, and myocardial inflammation after MI. Mechanistically, these protective effects were associated with an attenuated neuroimmune response in the paraventricular nucleus, which contributed to the decrease of sympathetic activity and attenuation of sympathetic remodeling in the heart. However, intragastric injection with PLX3397 obviously depleted macrophages and induced neutrophil and T-lymphocyte disorders in the heart, blood, and spleen. Conclusions Microglia depletion in the central nervous system attenuates pathological cardiac remodeling after MI by inhibiting neuroimmune response and sympathetic activity. Intragastric administration of PLX3397 leads to serious deleterious effects in peripheral immune cells, especially macrophages, which should be a cause for concern in animal experiments and clinical practice.

Resolvin D2 and its receptor GPR18 in cardiovascular and metabolic diseases: A promising biomarker and therapeutic target.

Accumulating evidence suggests that inflammation plays an important role in the pathophysiology of the initiation and progression of cardiovascular and metabolic diseases (CVMDs). Anti-inflammation strategies and those that promote inflammation resolution have gradually become potential therapeutic approaches for CVMDs. Resolvin D2 (RvD2), a specialized pro-resolving mediator, exerts anti-inflammatory and pro-resolution effects through its receptor GPR18, a G protein-coupled receptor. Recently, the RvD2/GPR18 axis has received more attention due to its protective role in CVMDs, including atherosclerosis, hypertension, ischaemiareperfusion, and diabetes. Here, we introduce basic information about RvD2 and GPR18, summarize their roles in different immune cells, and review the therapeutic potential of the RvD2/GPR18 axis in CVMDs. In summary, RvD2 and its receptor GPR18 play an important role in the occurrence and development of CVMDs and are potential biomarkers and therapeutic targets.

Kielin/chordin-like protein deficiency causes cardiac aging in male mice.

Previous studies have demonstrated that bone morphogenetic proteins (BMPs) play important roles in cardiovascular diseases, including atherosclerosis, artery calcification, myocardial remodeling, pulmonary arterial hypertension, and diabetic cardiomyopathy. Kielin/chordin-like protein (KCP) is a secreted protein that regulates the expression and function of BMPs. However, the role of KCP in cardiac aging remains unknown. In this study, we aimed to investigate the role of KCP in cardiac aging and its possible mechanisms. Echocardiogram showed that heart function was impaired in aged mice (24 months). In addition, analysis of heart structure showed that KCP knockout (KO) aggravated cardiac remodeling in aged mice. Moreover, KCP KO increased p-smad2/3 and TGF-ß expression, while decreased BMP-2 expression in aged mice. Furthermore, KCP KO increased the expression of cardiac senescence-related proteins in aged mice. KCP KO aggravated the imbalance of oxidants and antioxidants and increased the expression of proinflammatory cytokines and cardiomyocyte apoptosis in aged mice. Our study demonstrated that KCP KO aggravated cardiac aging in mice by increasing the levels of oxidative stress, inflammation, and cardiomyocyte apoptosis. KEY MESSAGE: KCP KO aggravated aging-related cardiac dysfunction and remodeling in male mice. KCP KO aggravated cardiac aging by increasing the levels of oxidative stress, inflammation, and cardiomyocyte apoptosis.

TRPA1 deficiency aggravates dilated cardiomyopathy by promoting S100A8 expression to induce M1 macrophage polarization in rats.

Transient receptor potential ankyrin 1 (TRPA1) plays an important role in different cardiovascular diseases. However, the role of TRPA1 in dilated cardiomyopathy (DCM) remains unclear. Here, we aimed to investigate the role of TRPA1 in DCM induced by doxorubicin (DOX) and explore its possible mechanisms. GEO data were used to explore the expression of TRPA1 in DCM patients. DOX (2.5 mg/kg/week, 6 weeks, i.p.) was used to induce DCM. Bone marrow-derived macrophages (BMDMs) and neonatal rat cardiomyocytes (NRCMs) were isolated to explore the role of TRPA1 in macrophage polarization, cardiomyocyte apoptosis, and pyroptosis. In addition, DCM rats were treated with the TRPA1 activator, cinnamaldehyde to explore the possibility of clinical translation. TRPA1 expression was increased in left ventricular (LV) tissue in DCM patients and rats. TRPA1 deficiency aggravated the cardiac dysfunction, cardiac injury, and LV remodeling in DCM rats. In addition, TRPA1 deficiency promoted the M1 macrophage polarization, oxidative stress, cardiac apoptosis, and pyroptosis induced by DOX. RNA-seq results showed that TRPA1 knockout promoted the expression of S100A8, an inflammatory molecule that belongs to the family of Ca2+ -binding S100 proteins, in DCM rats. Furthermore, S100A8 inhibition attenuated M1 macrophage polarization in BMDMs isolated from TRPA1 deficiency rats. Recombinant S100A8 promoted the apoptosis, pyroptosis, and oxidative stress in primary cardiomyocytes stimulated with DOX. Finally, TRPA1 activation via cinnamaldehyde alleviated the cardiac dysfunction and reduced S100A8 expression in DCM rats. Taken together, these results suggested that TRPA1 deficiency aggravates DCM by promoting S100A8 expression to induce M1 macrophage polarization and cardiac apoptosis.

IL-27p28 knockout aggravates Doxorubicin-induced cardiotoxicity by regulating Macrophage polarization.

BACKGROUND: Several interleukins (ILs) have been demonstrated to participate in cardiac injury. This study aimed to investigate whether IL-27p28 plays a regulatory role in doxorubicin (DOX)-induced cardiac injury by regulating inflammation and oxidative stress. METHODS: Dox was used to establish a mouse cardiac injury model, and IL-27p28 was knocked out to observe its role in cardiac injury. In addition, monocytes were adoptively transferred to clarify whether monocyte-macrophages mediate the regulatory role of IL-27p28 in DOX-induced cardiac injury. RESULTS: IL-27p28 knockout significantly aggravated DOX-induced cardiac injury and cardiac dysfunction. IL-27p28 knockout also upregulated the phosphorylation levels of p65 and STAT1 and promoted M1 macrophage polarization in DOX-treated mice, which increased cardiac inflammation and oxidative stress. Moreover, IL-27p28-knockout mice that were adoptively transferred WT monocytes exhibited worse cardiac injury and cardiac dysfunction and higher cardiac inflammation and oxidative stress. CONCLUSIONS: IL-27p28 knockdown aggravates DOX-induced cardiac injury by worsening the M1 macrophage/M2 macrophage imbalance and its associated inflammatory response and oxidative stress.

Scavenger Receptors in Myocardial Infarction and Ischemia/Reperfusion Injury: The Potential for Disease Evaluation and Therapy.

Scavenger receptors (SRs) are a structurally heterogeneous superfamily of evolutionarily conserved receptors that are divided into classes A to J. SRs can recognize multiple ligands, such as modified lipoproteins, damage-associated molecular patterns, and pathogen-associated molecular patterns, and regulate lipid metabolism, immunity, and homeostasis. According to the literature, SRs may play a critical role in myocardial infarction and ischemia/reperfusion injury, and the soluble types of SRs may be a series of promising biomarkers for the diagnosis and prognosis of patients with acute coronary syndrome or acute myocardial infarction. In this review, we briefly summarize the structure and function of SRs and discuss the association between each SR and ischemic cardiac injury in patients and animal models in detail. A better understanding of the effect of SRs on ischemic cardiac injury will inspire novel ideas for therapeutic drug discovery and disease evaluation in patients with myocardial infarction.

IL-12p40 deletion aggravates lipopolysaccharide-induced cardiac dysfunction in mice.

Background: Cardiac dysfunction is one of the most common complications of sepsis and is associated with the adverse outcomes and high mortality of sepsis patients. IL-12p40, the common subunit of IL-12 and IL-23, has been shown to be involved in a variety of inflammation-related diseases, such as psoriasis and inflammatory bowel disease. However, the role of IL-12p40 in lipopolysaccharide (LPS)-induced cardiac dysfunction remains obscure. This study aimed to explore the role of IL-12p40 in LPS-induced cardiac dysfunction and its potential mechanisms. Methods: In this study, mice were treated with LPS and the cardiac expression of IL-12p40 was determined. Then, IL-12p40-/- mice were used to detect the role and mechanisms of IL-12p40 in LPS-induced cardiac injury. In addition, monocytes were adoptively transferred to IL-12p40-/- mice to explore their effects on LPS-induced cardiac dysfunction. Results: The results showed that cardiac IL-12p40 expression was significantly increased after treated with LPS. In addition, IL-12p40 deletion significantly aggravated LPS-induced cardiac dysfunction, evidenced by the increased serum levels of cardiomyocyte injury markers and heart injury scores, as well as by the deteriorated cardiac function. Moreover, IL-12p40 deletion increased LPS-induced monocyte accumulation and cardiac expression of inflammatory cytokines, as well as enhanced the activation of the NF-κB and MAPK pathways. Furthermore, adoptive transfer WT mouse monocytes to IL-12p40-/- mice alleviated LPS-induced cardiac dysfunction and decreased the phosphorylation of p65. Conclusion: IL-12p40 deletion significantly aggravated LPS-induced cardiac injury and cardiac dysfunction in mice by regulating the NF-κB and MAPK signaling pathways, and this process was related to monocytes. Therefore, IL-12p40 show a protective role in SIC, and IL-12p40 deficiency or anti-IL-12p40 monoclonal antibodies may be detrimental to patients with SIC.

The role of semaphorins in cardiovascular diseases: Potential therapeutic targets and novel biomarkers.

Semaphorins (Semas), which belongs to the axonal guidance molecules, include 8 classes and could affect axon growth in the nervous system. Recently, semaphorins were found to regulate other pathophysiological processes, such as immune response, oncogenesis, tumor angiogenesis, and bone homeostasis, through binding with their plexin and neuropilin receptors. In this review, we summarized the detailed role of semaphorins and their receptors in the pathological progression of various cardiovascular diseases (CVDs), highlighting that semaphorins may be potential therapeutic targets and novel biomarkers for CVDs.

Mechanisms of efferocytosis in determining inflammation resolution: Therapeutic potential and the association with cardiovascular disease.

Efferocytosis is defined as the clearance of apoptotic cells (ACs) in physiological and pathological states and is performed by efferocytes, such as macrophages. Efferocytosis can lead to the resolution of inflammation and restore tissue homoeostasis; however, the mechanisms of efferocytosis in determining inflammation resolution are still not completely understood, and the effects of efferocytosis on other proresolving properties need to be explored and explained. In this review, the process of efferocytosis will be summarized briefly, and then these mechanisms and effects will be thoroughly discussed. In addition, the association between mechanisms of efferocytosis in determining resolution of inflammation and cardiovascular diseases will also be reviewed, as an understanding of this association may provide information on novel treatment targets.

Maresin-1 and its receptors RORα/LGR6 as potential therapeutic target for respiratory diseases.

Maresin-1 is one of the representative specialized pro-resolving mediators that has shown beneficial effects in inflammatory disease models. Recently, two distinct types of receptor molecules were discovered as the targets of maresin-1, further revealing the pro-resolution mechanism of maresin-1. One is retinoic acid-related orphan receptor α (RORα) and the another one is leucine-rich repeat domain-containing G protein-coupled receptor 6 (LGR6). In this review, we summarized the detailed role of maresin-1 and its two different receptors in respiratory diseases. RORα and LGR6 are potential targets for the treatment of respiratory diseases. Future basic research and clinical trials on MaR1 and its receptors should provide useful information for the treatment of respiratory diseases.