Rationale: Heart failure with preserved ejection fraction (HFpEF) can arise from hypertension-induced cardiac remodeling. Monocyte/macrophage accumulation and inflammation are crucial elements in the pathogenesis of hypertension-induced cardiac remodeling. The C-X-C chemokine receptor 4 (CXCR4) is a critical regulator of the macrophage-mediated immune response. Nevertheless, the contribution of CXCR4 to macrophage phenotype and function during the progression of HFpEF remains unclear. Herein, we aimed to determine the role of macrophagic CXCR4 in heart failure with preserved ejection fraction (HFpEF). Methods: As a HFpEF model, wild type mice and myeloid-specific CXCR4 deficiency mice were subjected to pressure overload for 30 days to assess the function of macrophagic CXCR4 on cardiac function. Medium from macrophages was used to treat cardiac fibroblasts to study macrophage-to-fibroblast signaling. Results: We found circulatory CXCR4+ immune cells, mainly monocytes, markedly increased in HFpEF patients with hypertension. In the experimental HFpEF mice model, macrophages but not neutrophils represent the main infiltrating inflammatory cells in the heart, abundantly expressing CXCR4. Myeloid-specific CXCR4 deficient impeded macrophage infiltration and inflammatory response in the heart of HFpEF mice, thus ameliorating cardiac fibrosis and improving cardiac diastolic function. Furthermore, transcriptomic profiling data revealed that CXCR4 loss in macrophages exhibited a decreased transcriptional signature associated with the regulation of inflammatory response. Notably, CXCR4 significantly augmented chemokine (C-X-C) motif ligand (CXCL3) expression, which at least partly contributed to fibrosis by promoting myofibroblast differentiation. Mechanistically, the increased production of pro-inflammatory cytokines in CXCR4 expressed macrophages could be attributed to the suppression of the peroxisome proliferator-activated receptor γ (PPARγ) activity. Conclusions: Collectively, our data supported that the infiltration of CXCR4+ macrophages in the heart exacerbates hypertension-induced diastolic function by promoting pro-inflammatory cytokines production and thus may serve as a potential therapeutic target for hypertension-induced HFpEF.

Chemokine C‐C motif ligand 7 (CCL7), a member of CC chemokine subfamily, plays pivotal roles in numerous inflammatory diseases. Hyper‐activation of inflammation is an important characteristic of abdominal aortic aneurysm (AAA). Therefore, in the present study, we aimed to determine the effect of CCL7 on AAA formation. CCL7 abundance in aortic tissue and macrophage infiltration were both increased in angiotensin II (Ang II)‐induced AAA mice. Ex vivo, CCL7 promoted macrophage polarization towards M1 phenotype. This effect was reversed by the blockage of CCR1, a receptor of CCL7. CCL7 up‐regulated JAK2/STAT1 protein level in macrophage, and CCL7‐induced M1 activation was suppressed by JAK2/STAT1 pathway inhibition. To verify the effect of CCL7 on AAA in vivo, either CCL7‐neutralizing antibody (CCL7‐nAb) or vehicles were intraperitoneally injected 24 hours prior to Ang II infusion and subsequently every three days for 4 weeks. CCL7‐nAb administration significantly attenuated Ang II‐induced luminal and external dilation as well as pathological remodelling. Immunostaining showed that CCL7‐nAb administration significantly decreased aneurysmal macrophage infiltration. In conclusion, CCL7 contributed to Ang II‐induced AAA by promoting M1 phenotype of macrophage through CCR1/JAK2/STAT1 signalling pathway.

BackgroundGlobal and national estimates on the epidemiology of aortic aneurysms are prerequisites for disease management and policymaking. Based on the Global Burden of Disease (GBD) 2019, this study aimed to discern the global aortic aneurysm burden by systematically analyzing demographic data on mortality and exploring the attributable risks and relevant factors.MethodsThe data analyzed in this study were available in the Global Health Data Exchange (GHDx) online query tool. The population in our study comprised individuals from 204 countries and territories from 1990 to 2019. The estimated annual percentage changes (EAPCs) were performed to assess the temporal trends of aortic aneurysms and their attributable risks. Spearman correlation analysis was performed to explore the relationship between the burden of aortic aneurysm and covariates.ResultsAlthough aortic aneurysm-related deaths (82.1%) and disability-adjusted life years (DALYs) (67%) increased from 1990 to 2019, the global trend of age-standardized rate of death (ASRD) (EAPC: −1.34, 95% CI = −1.46 to −1.22, P < 0.001) and age-standardized rate of DALY (ASDALYR) (EAPC: −1.06, 95% CI = −1.17 to −0.95, P < 0.001) decreased, both of which presented age dependence and gender differences. Smoking and high systolic blood pressure (SBP) were the main attributable risks of disease burden and tend to decease globally (EAPC: −1.89, 95% CI = −2.03 to −1.89, P < 0.001; −1.31 95% CI = −1.43 to −1.19, P < 0.001, respectively). Alcohol abstinence (male: R = −0.71, P < 0.001; female: R = −0.73, P < 0.001), smoking age of initiation (male: R = −0.32, P < 0.001; female: R = −0.50, P < 0.001), physical activity (male: R = −0.50, P < 0.001; female: R = −0.55, P < 0.001), and mean temperature (R = −0.62, P < 0.001) had negative correlation with ASRD. However, cholesterol level (male: R = 0.62, P < 0.001; female: R = 0.39, P < 0.001), body mass index (BMI) (male: R = 0.30, P < 0.001; female R = −0.01, P > 0.05), and alcohol consumption (male: R = 0.46, P < 0.001; female: R = 0.42, P < 0.001) had a positive correlation with ASRM. Besides, standard of living and medical resources positively related to burden of aortic aneurysm.ConclusionIn this study, a decreasing trend of aortic aneurysm burden was found globally, especially in advanced regions. Aged men who smoke and women who have hypertension should pay close attention to, particularly in deprived economic groups, and many approaches can be performed to reduce the burden of aortic aneurysms.

Cardiac dysfunction is a common complication of sepsis with high mortality. The present study was designed to identify the effect of neutrophil-derived lipocalin-2 (LCN2) in septic cardiac dysfunction (SCD) and its potential mechanism. Wild-type (WT) and LCN2-knockout (LCN2 KO) mice were peritoneally injected with lipopolysaccharide (LPS) to induce SCD. The cardiac function was assessed 12 h after LPS injection by echocardiography. Cardiac tissue was harvested for the evaluation of malonaldehyde (MDA) and prostaglandin E synthase 2 (PTGS2) mRNA levels. LPS induced ferroptosis and SCD in mice. LCN2 deficiency attenuated cardiac injury post-LPS administration. In vitro, LCN2 expression in neutrophils increased in response to LPS. Ferroptosis of cardiomyocytes induced by conditioned medium (CM) from LPS-induced neutrophils of WT mice could be attenuated in CM from LPS-induced neutrophils of LCN2 KO mice. Exogenous LCN2 induced H9C2 cell ferroptosis via increasing labile iron pool (LIP). In conclusion, our results showed that LCN2 deficiency prevented heart dysfunction and ferroptosis in SCD mice and suggested that neutrophil-derived LCN2 might be a promising therapeutic target for SCD.

Cardiac ankyrin repeat protein (CARP) is a cardiac‐specific stress‐response protein which exerts diverse effects to modulate cardiac remodeling in response to pathological stimuli. We examined the role of CARP in postnatal cardiac development and function under basal conditions in mice. Transgenic mice that selectively overexpressed CARP in heart (CARP Tg) exhibited dilated cardiac chambers, impaired heart function, and cardiac fibrosis as assessed by echocardiography and histological staining. Furthermore, the mice had a shorter lifespan and reduced survival rate in response to ischemic acute myocardial infarction. Immunofluorescence demonstrated the overexpressed CARP protein was predominantly accumulated in the nuclei of cardiomyocytes. Microarray analysis revealed that the nuclear localization of CARP was associated with the suppression of calcium‐handling proteins. In vitro experiments revealed that CARP overexpression resulted in decreased cell contraction and calcium transient. In post‐mortem cardiac specimens from patients with dilated cardiomyopathy and end‐stage heart failure, CARP was significantly increased. Taken together, our data identified CARP as a crucial contributor in dilated cardiomyopathy and heart failure which was associated with its regulation of calcium‐handling proteins.