ACE2 Rescues Sepsis-Associated Encephalopathy by Reducing Inflammation, Oxidative Stress, and Neuronal Apoptosis via the Nrf2/Sestrin2 Signaling Pathway.

Neuroinflammation and oxidative stress contribute to the progression of sepsis-associated encephalopathy (SAE). Angiotensin-converting enzyme 2 (ACE2) is considered to be a neuroprotective factor due to its anti-inflammatory and antioxidant properties. However, the role of ACE2 on myeloid cells in regulating SAE and the underlying mechanism warrants further exploration. SAE was induced in ACE2 transgenic (TG), knockout (KO), and bone marrow (BM) chimeric mice by cecal ligation and puncture (CLP). The expression levels of apoptosis-, oxidation- and neuroinflammation-associated mediators and morphological changes were monitored by quantitative real-time PCR analyses and histological examinations in the cortex of septic mice. The contents of angiotensin (Ang) II and Ang-(1-7) along with the activity of ACE2 were examined with commercial kits. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Sestrin2 was detected by immunoblotting analysis. Our results indicated that the expression of cortical ACE2 was significantly reduced in the early phase of CLP-induced sepsis. Moreover, ACE2 overexpression in TG mice conferred neuroprotection against sepsis, as evidenced by alleviated neuronal apoptosis, oxidative stress, and proinflammatory M1-like microglial polarization, accompanied by upregulation of the Ang-(1-7), Nrf2, and Sestrin2 protein levels. Conversely, ACE2 deficiency in KO mice exacerbated SAE. The neuroprotective effects of ACE2 were further confirmed in wild-type mice transplanted with ACE2-TG and KO BM cells. Therefore, our data suggest that myeloid ACE2 exerts a protective role in the pathogenesis of SAE, potentially by activating Ang-(1-7)-Nrf2/sestrin2 signaling pathway, and highlight that upregulating ACE2 expression and activity may represent a promising approach for the treatment of SAE in patients with sepsis.

Research Progress of Hippocampal Dopamine System Changes in Perioperative Neurocognitive Disorders.

Perioperative neurocognitive disorders (PND) are a cognitive impairment that occurs after anesthesia, especially in elderly patients and significantly affects their quality of life. The hippocampus, as a critical region for cognitive function and an important location in PND research, has recently attracted increasing attention. However, in the hippocampus the impact of anesthesia and its underlying mechanisms remain unclear. This review focuses on investigation of the effects of anesthesia on the hippocampal dopamine (DA) system and explores its potential association with PND. Through comprehensive review of existing studies, it was found that anesthesia affects the hippocampus through various pathways involved in metabolism, synaptic plasticity and oxygenation. Anesthesia may also influence the DA neurotransmitter system in the brain which plays a role in emotions, rewards, learning and memory functions. Specifically, anesthesia may participate in the pathogenesis of PND by affecting the DA system within the hippocampus. Future studies should explore the molecular mechanisms of these effects through techniques such as neuroimaging to study real-time effects to improve animal models to better simulate clinical observations. For clinical application, it is recommended that physicians exercise caution when selecting and managing anesthetic drugs by adopting comprehensive cognitive assessment methods to reduce post-anesthesia cognitive risk. Overall, this review provides a better understanding of the relationship between the hippocampal DA system and perioperative neurocognitive function and provides valuable guidance for prevention and treatment strategies for PND.

Mac-1 deficiency ameliorates pressure overloaded heart failure through inhibiting macrophage polarization and activation.

Persistent pressure overload commonly leads to pathological cardiac hypertrophy and remodeling, ultimately leading to heart failure (HF). Cardiac remodeling is associated with the involvement of immune cells and the inflammatory response in pathogenesis. The macrophage-1 antigen (Mac-1) is specifically expressed on leukocytes and regulates their migration and polarization. Nonetheless, the involvement of Mac-1 in cardiac remodeling and HF caused by pressure overload has not been determined. The Mac-1-knockout (KO) and wild-type (WT) mice were subjected to transverse aortic constriction (TAC) for 6 weeks. Echocardiography and pressure-volume loop assessments were used to evaluate cardiac function, and cardiac remodeling and macrophage infiltration and polarization were estimated by histopathology and molecular techniques. The findings of our study demonstrated that Mac-1 expression was markedly increased in hearts subjected to TAC treatment. Moreover, compared with WT mice, Mac-1-KO mice exhibited dramatically ameliorated TAC-induced cardiac dysfunction, hypertrophy, fibrosis, oxidative stress and apoptosis. The potential positive impacts may be linked to the inhibition of macrophage infiltration and M1 polarization via reductions in NF-kB and STAT1 expression and upregulation of STAT6. In conclusion, this research reveals a new function of Mac-1 deficiency in reducing pathological cardiac remodeling and HF caused by pressure overload. Additionally, inhibiting Mac-1 could be a potential treatment option for patients with HF in a clinical setting.

ACE2 Expressed on Myeloid Cells Alleviates Sepsis-Induced Acute Liver Injury via the Ang-(1-7)-Mas Receptor Axis.

Sepsis-induced acute liver injury (ALI) is common in intensive care units. Angiotensin-converting enzyme 2 (ACE2) plays a vital role in hepatic fibrosis and steatosis; however, its role in sepsis-induced ALI remains unclear. This study found that hepatic ACE2 expression in cecal ligation and puncture (CLP)-treated mice significantly decreased 24 h after CLP. ACE2-transgenic (TG) mice exhibited a significant improvement in CLP-induced ALI, accompanied by the inhibition of hepatocyte apoptosis, oxidative stress, and inflammation, while ACE2-knockout mice demonstrated an opposite trend. During sepsis-induced ALI, ACE2-TG could also elevate the Ang-(1-7) and Mas receptor (MasR) levels in liver tissues. Interestingly, the MasR inhibitor A779 abrogated the favorable effects of ACE2 on CLP-induced ALI. In a bone marrow transplantation experiment, the ACE2-TG transplantation group showed significantly improved inflammation and liver dysfunction, less hepatocyte apoptosis, and reduced oxidative stress after CLP compared with the wild-type transplantation group. In contrast, the ACE2-knockout group showed poor inflammatory response and liver dysfunction, significantly more hepatocyte apoptosis, and elevated oxidative stress than the wild-type transplantation group after CLP. ACE2 protects against sepsis-induced ALI by inhibiting hepatocyte apoptosis, oxidative stress, and inflammation via the Ang-(1-7)-Mas receptor axis. Thus, targeting ACE2 may be a promising novel strategy for preventing and treating sepsis-induced ALI.

CD11b mediates hypertensive cardiac remodeling by regulating macrophage infiltration and polarization.

INTRODUCTION: Leukocyte infiltration is an early event during cardiac remodeling frequently leading to heart failure (HF). Integrins mediate leukocyte infiltration during inflammation. However, the importance of specific integrins in hypertensive cardiac remodeling is still unclear. OBJECTIVES: To elucidate the significance of CD11b in hypertensive cardiac remodeling. METHODS: Angiotensin (Ang II) or deoxycorticosterone acetate (DOCA)-salt was used to induce cardiac remodeling in mice of gene knockout (KO), bone marrow (BM) chimera, and the CD11b neutralizing antibody or agonist leukadherin-1 (LA1) treatment. RESULTS: Our microarray data showed that integrin subunits Itgam (CD11b) and Itgb2 (CD18) were the most highly upregulated in Ang II-infused hearts. CD11b expression and CD11b/CD18+ myelomonocytes were also time-dependently increased. KO or pharmacological blockade of CD11b greatly attenuated cardiac remodeling and macrophage infiltration and M1 polarization induced by Ang II or DOCA-salt. This protection was verified in wild-type mice transplanted with CD11b-deficient BM cells. Conversely, administration of CD11b agonist LA1 showed the opposite effects. Further, CD11b KO reduced Ang II-induced macrophage adhesion and M1 polarization, leading to reduction of cardiomyocyte enlargement and fibroblast differentiation in vitro. The numbers of CD14+CD11b+CD18+ monocytes and CD15+CD11b+CD18+ granulocytes were obviously higher in HF patients than in normal controls. CONCLUSION: Our data demonstrate an important role of CD11b+ myeloid cells in hypertensive cardiac remodeling, and suggest that HF may benefit from targeting CD11b.

N-arachidonoylphenolamine alleviates ischaemia/reperfusion-induced cardiomyocyte necroptosis by restoring proteasomal activity.

Necroptosis and apoptosis contribute to the pathogenesis of myocardial ischaemia/reperfusion (I/R) injury and subsequent heart failure. N-arachidonoylphenolamine (AM404) is a paracetamol lipid metabolite that has pleiotropic activity to modulate the endocannabinoid system. However, the protective role of AM404 in modulating I/R-mediated myocardial damage and the underlying mechanism remain largely unknown. A murine I/R model was generated by occlusion of the left anterior descending artery. AM404 (20 mg/kg) was injected intraperitoneally into mice at 2 and 24 h before the I/R operation. Our data revealed that AM404 administration to mice greatly ameliorated I/R-triggered impairment of myocardial performance and reduced infarct area, myocyte apoptosis, oxidative stress and inflammatory response accompanied by the reduction of receptor interacting protein kinase (RIPK)1/3- mixed lineage kinase domain-like (MLKL)-mediated necroptosis and upregulation of the immunosubunits (ß2i and ß5i). In contrast, administration of epoxomicin (a proteasome inhibitor) dramatically abolished AM404-dependent protection against myocardial I/R damage. Mechanistically, AM404 treatment increases ß5i expression, which interacts with Pellino-1 (Peli1), an E3 ligase, to form a complex with RIPK1/3, thereby promoting their degradation, which leads to inhibition of cardiomyocyte necroptosis in the I/R heart. In conclusion, these findings demonstrate that AM404 could prevent cardiac I/R damage and may be a promising drug for the treatment of ischaemic heart disease.

Myeloid ACE2 protects against septic hypotension and vascular dysfunction through Ang-(1-7)-Mas-mediated macrophage polarization.

Angiotensin converting enzyme 2 (ACE2) is a new identified member of the renin-angiotensin-aldosterone system (RAAS) that cleaves angiotensin II (Ang II) to Ang (1-7), which exerts anti-inflammatory and antioxidative activities via binding with Mas receptor (MasR). However, the functional role of ACE2 in sepsis-related hypotension remains unknown. Our results indicated that sepsis significantly reduced blood pressure and led to disruption between ACE-Ang II and ACE2-Ang (1-7) balance. ACE2 knock-in mice exhibited improved sepsis-induced mortality, hypotension and vascular dysfunction, while ACE2 knockout mice exhibited the opposite effects. Bone marrow transplantation and in vitro experiments confirmed that myeloid ACE2 exerted a protective role by suppressing oxidative stress, NO production and macrophage polarization via the Ang (1-7)-MasR-NF-κB and STAT1 pathways. Thus, ACE2 on myeloid cells could protect against sepsis-mediated hypotension and vascular dysfunction, and upregulating ACE2 may represent a promising therapeutic option for septic patients with hypotension.

ACE2 activation alleviates sepsis-induced cardiomyopathy by promoting MasR-Sirt1-mediated mitochondrial biogenesis.

Sepsis-induced cardiomyopathy (SIC), caused by a dysregulated host response to infection, is a major contributor to high mortality. Angiotensin-converting enzyme 2 (ACE2), a crucial component of the renin-angiotensin system (RAS), has protective effects against several cardiovascular diseases, such as myocardial infarction and heart failure. However, the role of ACE2 in the pathogenesis of SIC and underlying mechanisms remain unknown. The present study was designed to examine the effects of ACE2 activation or inhibition on SIC in C57BL/6 mice. The ACE2 activator diminazene aceturate (DIZE) and ACE2 inhibitor MLN-4760 were applied for treatment. Myocardial function, inflammatory response, oxidative stress, apoptosis and mitochondrial biogenesis were investigated. Major assays were echocardiography, H&E staining, immunofluorescence staining, DHE staining, TUNEL staining, Western blot, qPCR analysis, ELISA and corresponding kits. We confirmed that ACE2 was markedly downregulated in septic heart tissues. Pharmacological activation of ACE2 by DIZE ameliorated cecal ligation puncture (CLP)-induced mortality, cardiac dysfunction, inflammatory response, oxidative stress and the cardiomyocyte apoptosis by promoting MasR-Sirt1-mediated mitochondrial biogenesis. In contrast, SIC was aggravated via inhibiting MasR-Sirt1-mediated mitochondrial biogenesis by the use of ACE2 inhibitor MLN-4760. Consequently, activation of ACE2 may protect against SIC by promoting MasR-Sirt1-mediated mitochondrial biogenesis.

Caffeine intake interacts with Asian gene variants in Parkinson's disease: a study in 4488 subjects.

Background: Caffeine intake reduces risk of Parkinson's disease (PD), but the interaction with genes is unclear. The interaction of caffeine with genetic variants in those at high PD risk has healthcare importance. We investigate interactions of caffeine intake with risk variants found in Asians, and determine PD risk estimates in caffeine-drinkers carrying these variants. Methods: PD patients and controls without neurological disorders were included. Caffeine intake was assessed using a validated evaluation tool. Leucine rich repeat kinase 2 (LRRK2) risk variants were genotyped. Statistical analysis was conducted with logistic regression models. Gene-caffeine interactions were quantified using attributable proportion (AP) due to interaction (positive interaction defined as AP >0). Findings: 5100 subjects were screened and 4488 subjects (1790 PD, 2698 controls) with genetic data of at least one LRRK2 variant were included. Risk-variant-carriers who were non-caffeine-drinkers had increased PD odds compared to wildtype carriers who were caffeine-drinkers for G2385R [OR 8.6 (2.6-28.1) p < 0.001; AP = 0.71], R1628P [OR 4.6 (1.6-12.8) p = 0.004; AP = 0.50] and S1647T [OR 4.0 (2.0-8.1) p < 0.001; AP = 0.55] variants. Interpretation: Caffeine intake interacts with LRRK2 risk variants across three different groups of gene carriers. Asymptomatic risk-variant-carriers who are non-caffeine-drinkers have four to eight times greater PD risk compared to wildtype-caffeine-drinkers. Lifestyle modifications to mitigate PD risk in asymptomatic healthy risk variant carriers have potential roles in our Asian cohort. Funding: This study was supported by the National Medical Research Council (STaR and PD OF LCG 000207 grants) and Duke-NUS Medical School.

TCH-165 attenuates cardiac ischaemia/reperfusion injury by balancing mitochondrial dynamics via increasing proteasome activity.

The proteasome is the main complex responsible for maintaining intracellular protein homeostasis, impairment of which is associated with cardiac ischaemia/reperfusion (I/R) injury. The small molecule TCH-165 has been found to activate the 20S proteasome to remove disordered proteins in multiple myeloma and glioblastoma. However, the preventive effect of TCH-165 against I/R-mediated cardiac impairment in mice remains largely unknown. Here, a cardiac I/R model was established in mice. Heart function was assessed with echocardiography. Cardiac infarction, myocyte death, and superoxide level were evaluated by 2,3,5-triphenyltetrazolium chloride (TTC)-Evans blue staining, terminal deoxynucleotidyl transferase-mediated dUTP nick and labelling (TUNEL) assay and immunostaining, respectively. Our results showed that TCH-165 treatment markedly ameliorated I/R-mediated cardiac dysfunction and decreased the infarct size, apoptosis, and superoxide levels. Mechanistically, TCH-165 increased immunoproteasome subunit expression/activity, increasing pro-fission protein dynamin-1-like protein (DNM1L, also known as DRP1) degradation and the expression of the pro-fusion proteins mitofusin 1/2 (Mfn1/2) and thereby leading to mitochondrial fission/fusion balance. In vitro experiments confirmed that inhibition of proteasome activity by epoxomicin abolished the protective effect of TCH-165 against hypoxia/reoxygenation (H/R)-induced increases in cardiomyocyte apoptosis, superoxide production and mitochondrial fission. In summary, TCH-165 is a newly discovered inducer of immunoproteasome activity that exerts a preventive effect against cardiac I/R damage by targeting Drp1 degradation, indicating that it may be as a potential therapeutic candidate for ischaemic heart disease.

Blockage of S100A8/A9 ameliorates septic nephropathy in mice.

Septic acute kidney injury (AKI) is the commonest cause of complication of sepsis in intensive care units, but its pathophysiology remains unclear. Calprotectin (S100A8/A9), which is a damage-associated molecular patterns (DAMPs) molecule, exerts a critical role in modulating leukocyte recruitment and inflammatory response during various diseases. However, role of S100A8/A9 in septic AKI is largely unknown. In this research, Septic AKI was triggered by cecal ligation and puncture (CLP) operation in wild-type mice, which treated with or without an S100A9 inhibitor, Paquinimod (Paq, 10 mg/kg) that prevents S100A8/A9 to bind to Toll-like receptor 4 (TLR4). Renal function, pathological changes, cell death, and oxidative stress were evaluated. Our research indicated that the mRNA and protein expression of S100A9 are time-dependently elevated in the kidney following CLP. Moreover, the administration of Paq for 24 h significantly improved CLP-induced renal dysfunction and pathological alterations compared with vehicle treatment in mice. These beneficial effects were associated with the inhibition of CLP-triggered renal tubular epithelial cell apoptosis, inflammation, superoxide production, and mitochondrial dynamic imbalance. What's more, we further confirmed the above findings by cell co-culture experiments. Our study demonstrates that S100A9 is a prominent protein to lead to septic AKI, and the selective inhibition of S100A9 could represent a new therapeutic approach which can treat septic AKI.

The immunoproteasome subunit ß2i ameliorates myocardial ischemia/reperfusion injury by regulating Parkin-Mfn1/2-mediated mitochondrial fusion.

Mitochondrial dynamics are critical for maintaining mitochondrial morphology and function during cardiac ischemia and reperfusion (I/R). The immunoproteasome complex is an inducible isoform of the proteasome that plays a key role in modulating inflammation and some cardiovascular diseases, but the importance of immunoproteasome catalytic subunit ß2i (also known as LMP10 or MECL1) in regulating mitochondrial dynamics and cardiac I/R injury is largely unknown. Here, using ß2i-knockout (KO) mice and rAAV9-ß2i-injected mice, we discovered that ß2i expression and its trypsin-like activity were significantly attenuated in the mouse I/R myocardium and in patients with myocardial infarction (MI). Moreover, ß2i-KO mice exhibited greatly enhanced I/R-mediated cardiac dysfunction, infarct size, myocyte apoptosis and oxidative stress accompanied by excessive mitochondrial fission due to Mfn1/2 and Drp1 imbalance. Conversely, cardiac overexpression of ß2i in mice injected with recombinant adeno-associated virus 9 (rAAV9)-ß2i ameliorated cardiac I/R injury. Mechanistically, I/R injury reduced ß2i expression and activity, which increased the expression of the E3 ligase Parkin protein and promoted the degradation of mitofusin 1/2 (Mfn1/2), leading to excessive mitochondrial fission. In conclusion, our data suggest for the first time that ß2i exerts a protective role against cardiac I/R injury and that increasing ß2i expression may be a new therapeutic option for cardiac ischemic disease in clinical practice. Graphical abstract showing how the immunoproteasome subunit ß2i ameliorates myocardial I/R injury by regulating Parkin-Mfn1/2-mediated mitochondrial fusion.

Serial deep gray nuclear DTI changes in Parkinson's disease over twelve years.

Background: Deep gray nuclear pathology relates to motor deterioration in idiopathic Parkinson's disease (PD). Inconsistent deep nuclear diffusion tensor imaging (DTI) findings in cross-sectional or short-term longitudinal studies have been reported. Long-term studies in PD are clinically challenging; decade-long deep nuclear DTI data are nonexistent. We investigated serial DTI changes and clinical utility in a case-control PD cohort of 149 subjects (72 patients/77 controls) over 12 years. Methods: Participating subjects underwent brain MRI at 1.5T; DTI metrics from segmented masks of caudate, putamen, globus pallidus and thalamus were extracted from three timepoints with 6-year gaps. Patients underwent clinical assessment, including Unified Parkinson Disease Rating Scale Part 3 (UPDRS-III) and Hoehn and Yahr (H&Y) staging. A multivariate linear mixed-effects regression model with adjustments for age and gender was used to assess between-group differences in DTI metrics at each timepoint. Partial Pearson correlation analysis was used to correlate clinical motor scores with DTI metrics over time. Results: MD progressively increased over time and was higher in the putamen (p < 0.001) and globus pallidus (p = 0.002). FA increased (p < 0.05) in the thalamus at year six, and decreased in the putamen and globus pallidus at year 12. Putaminal (p = 0.0210), pallidal (p = 0.0066) and caudate MD (p < 0.0001) correlated with disease duration. Caudate MD (p < 0.05) also correlated with UPDRS-III and H&Y scores. Conclusion: Pallido-putaminal MD showed differential neurodegeneration in PD over 12 years on longitudinal DTI; putaminal and thalamic FA changes were complex. Caudate MD could serve as a surrogate marker to track late PD progression.

MK-886 protects against cardiac ischaemia/reperfusion injury by activating proteasome-Keap1-NRF2 signalling.

Oxidative stress is considered a key factor contributing to the initiation and development of cardiac injury following ischaemia‒reperfusion (I/R). Arachidonate 5-lipoxygenase (ALOX5) is a rate-limiting enzyme for leukotriene biosynthesis. MK-886 is an inhibitor of ALOX5 that exhibits anti-inflammatory and antioxidant activities. However, the significance of MK-886 in preventing I/R-mediated cardiac injury and the underlying mechanism remain unclear. Cardiac I/R model was produced by ligation/release of the left anterior descending artery. MK-886 (20 mg/kg) was administered intraperitoneally into mice at 1 and 24 h before I/R. Our results indicated that MK-886 treatment significantly attenuated I/R-mediated cardiac contractile dysfunction and decreased the infarct area, myocyte apoptosis, and oxidative stress accompanied with reduction of Kelch-like ECH-associated protein 1 (keap1) and upregulation of nuclear factor erythroid 2-related factor 2 (NRF2). Conversely, administration of the proteasome inhibitor epoxomicin and NRF2 inhibitor ML385 greatly abrogated MK-886-mediated cardioprotection after I/R injury. Mechanistically, MK-886 enhanced the expression of the immunoproteasome subunit ß5i, which interacted with keap1 and enhanced its degradation, leading to activation of the NRF2-dependent antioxidant response and improvement of mitochondrial fusion-fission balance in the I/R-treated heart. In summary, our present findings indicated that MK-886 could protect the heart against I/R injury and highlight that MK-886 may represent a promising therapeutic candidate for preventing ischaemic disease.

Ursolic Acid Ameliorates Myocardial Ischaemia/Reperfusion Injury by Improving Mitochondrial Function via Immunoproteasome-PP2A-AMPK Signalling.

Cardiac ischaemia/reperfusion (I/R) injury causes cardiomyocyte apoptosis and mitochondrial dysfunction. Ursolic acid (UA), as a pentacyclic triterpenoid carboxylic acid, exerts several bioactivities in animal models of different diseases, but the preventive role of UA in I/R-induced myocardial dysfunction remains largely unknown. Male wild-type mice were pre-administered with UA at a dosage of 80 mg/kg i.p. and then subjected to cardiac I/R injury for 24 h. Cardiac function and pathological changes were examined by echocardiography and histological staining. The protein and mRNA levels of the genes were determined using qPCR and immunoblotting analysis. Our results revealed that UA administration in mice significantly attenuated the I/R-induced decline in cardiac function, infarct size, myocyte apoptosis, and oxidative stress. Mechanistically, UA increased three immunoproteasome catalytic subunit expressions and activities, which promoted ubiquitinated PP2A degradation and activated AMPK-PGC1α signalling, leading to improved mitochondrial biosynthesis and dynamic balance. In vitro experiments confirmed that UA treatment prevented hypoxia/reperfusion (H/R)-induced cardiomyocyte apoptosis and mitochondrial dysfunction through activation of AMPK signalling. In summary, our findings identify UA as a new activator of the immunoproteasome that exerts a protective role in I/R-induced myocardial dysfunction and suggest that UA supplementation could be beneficial for the prevention of cardiac ischaemic disease.

Adipose Triglyceride Lipase Deficiency Aggravates Angiotensin II-Induced Atrial Fibrillation by Reducing Peroxisome Proliferator-Activated Receptor α Activation in Mice.

Atrial fibrillation (AF) is a main risk factor for cerebrovascular diseases but lacks precision therapy. Adipose triglyceride lipase (ATGL) is a key enzyme involved in the intracellular degradation of triacylglycerol and plays an important role in lipid and energy metabolism. However, the role of ATGL in the regulation of AF remains unclear. In this study, AF was induced by infusion of angiotensin II (Ang II, 2000 ng/kg/min) for 3 weeks in male ATGL knockout (KO) mice and age-matched C57BL/6 wild-type mice. The atrial volume was measured by echocardiography. Atrial fibrosis, inflammatory cells, and superoxide production were detected by histologic examinations. The results showed that ATGL expression was significantly downregulated in the atrial tissue of the Ang II-infused mice. Moreover, Ang II-induced increase in the inducibility and duration of AF, atrial dilation, fibrosis, inflammation, and oxidative stress in wild-type mice were markedly accelerated in ATGL KO mice; however, these effects were dramatically reversed in the ATGL KO mice administered with peroxisome proliferator-activated receptor (PPAR)-α agonist clofibric acid. Mechanistically, Ang II downregulated ATGL expression and inhibited PPAR-α activity, activated multiple signaling pathways (inhibiting kappa B kinase α/ß-nuclear factor-κB, nicotinamide adenine dinucleotide phosphate oxidase, and transforming growth factor-ß1/SMAD2/3) and reducing Kv1.5, Cx40, and Cx43 expression, thereby contributing to atrial structural and electrical remodeling and subsequent AF. In summary, our results indicate that ATGL KO enhances AF inducibility, possibly through inhibiting PPAR-α activation and suggest that activating ATGL might be a new therapeutic option for treating hypertensive AF.

S100a8/a9 contributes to sepsis-induced cardiomyopathy by activating ERK1/2-Drp1-mediated mitochondrial fission and respiratory dysfunction.

Sepsis-induced cardiomyopathy (SIC) is the main complication and a leading cause of death in intensive care units. S100a8/a9 is a calcium-binding protein that participates in various inflammatory diseases; however, its role in sepsis-induced cardiomyopathy and the underlying mechanism remains to be explored. Here, septic cardiomyopathy was induced with cecal ligation and puncture (CLP) in S100a9-knockout (KO) mice lacking the heterodimer S100a8/a9 or wild-type (WT) mice administered with an S100a9-specific inhibitor Paquinimod (Paq), which prevents the binding of S100a9 toTLR4. Our results showed that S100a8/a9 expression in the heart peaked 24 h following the CLP operation, declined at 48 h and returned to baseline at 72 h. Loss of S100a9 by knockout in mice protected against CLP-induced mortality, cardiac dysfunction, myocyte apoptosis, recruitment of Mac-2+ macrophages, superoxide production, and the expression of pro-inflammatory cytokines genes compared with WT mice. Moreover, S100a9-KO significantly attenuated CLP-induced activation of the ERK1/2-Drp1 (S616) pathway, excessive mitochondrial fission, and mitochondrial respiration dysfunction. In contrast, activation of ERK1/2 with its agonist tBHQ reversed the inhibitory effects of S100a9-knockout on CLP-induced cardiomyopathy and mitochondrial dysfunction. Finally, administration of Paq to WT mice markedly prevented the CLP-induced cardiomyopathy mitochondrial fission and dysfunction compared with vehicle control. In summary, our data reveal, for the first time, that S100a8/a9 plays a critical role in mediating SIC, presumably by activating TLR4-ERK1/2-Drp1-dependent mitochondrial fission and dysfunction and highlight that blockage of S100a8/a9 may be a promising therapeutic strategy to prevent SIC in patients with sepsis.