Cellular and molecular characteristics of stromal Lkb1 deficiency-induced gastrointestinal polyposis based on single-cell RNA sequencing.

Liver kinase B1 (Lkb1), encoded by serine/threonine kinase (Stk11), is a serine/threonine kinase and tumor suppressor that is strongly implicated in Peutz-Jeghers syndrome (PJS). Numerous studies have shown that mesenchymal-specific Lkb1 is sufficient for the development of PJS-like polyps in mice. However, the cellular origin and components of these Lkb1-associated polyps and underlying mechanisms remain elusive. In this study, we generated tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 and Lkb1flox/flox;PDGFRα-Cre/ERT2 mice, performed single-cell RNA sequencing (scRNA-seq) and imaging-based lineage tracing, and aimed to investigate the cellular complexity of gastrointestinal polyps associated with PJS. We found that Lkb1flox/+;Myh11-Cre/ERT2 mice developed gastrointestinal polyps starting at 9 months after tamoxifen treatment. scRNA-seq revealed aberrant stem cell-like characteristics of epithelial cells from polyp tissues of Lkb1flox/+;Myh11-Cre/ERT2 mice. The Lkb1-associated polyps were further characterized by a branching smooth muscle core, abundant extracellular matrix deposition, and high immune cell infiltration. In addition, the Spp1-Cd44 or Spp1-Itga8/Itgb1 axes were identified as important interactions among epithelial, mesenchymal, and immune compartments in Lkb1-associated polyps. These characteristics of gastrointestinal polyps were also demonstrated in another mouse model, tamoxifen-inducible Lkb1flox/flox;PDGFRα-Cre/ERT2 mice, which developed obvious gastrointestinal polyps as early as 2-3 months after tamoxifen treatment. Our findings further confirm the critical role of mesenchymal Lkb1/Stk11 in gastrointestinal polyposis and provide novel insight into the cellular complexity of Lkb1-associated polyp biology. © 2024 The Pathological Society of Great Britain and Ireland.

Renal and cardiac effects of the PDE9 inhibitor BAY 73-6691 in 5/6 nephrectomized rats.

It has been suggested that the novel selective phosphodiesterase 9 (PDE9) inhibitor may improve cardiac and renal function by blocking 3',5'-cyclic guanosine monophosphate (cGMP) degradation. 5/6 nephrectomized (5/6Nx) rats were used to investigate the effects of the PDE9 inhibitor (BAY 73-6691) on the heart and kidney. Two doses of BAY 73-6691 (1 mg/kg/day and 5 mg/kg/day) were given for 95 days. The 5/6Nx rats developed albuminuria, a decrease in serum creatinine clearance (Ccr), and elevated serum troponin T levels. Echocardiographic data showed that 5/6 nephrectomy resulted in increased fractional shortening (FS), stroke volume (SV), and left ventricular ejection fraction (EF). However, 95 days of PDE9 inhibitor treatment did not improve any cardiac and renal functional parameter. Histopathologically, 5/6 nephrectomy resulted in severe kidney and heart damage, such as renal interstitial fibrosis, glomerulosclerosis, and enlarged cardiomyocytes. Telmisartan attenuated renal interstitial fibrosis and glomerulosclerosis as well as improved cardiomyocyte size. However, except for cardiomyocyte size and renal perivascular fibrosis, BAY 73-6691 had no effect on other cardiac and renal histologic parameters. Pathway enrichment analysis using RNA sequencing data of kidney and heart tissue identified chronic kidney disease pathways, such as phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway, complement and coagulation cascades, and nuclear factor kappa B (NF-κB) signaling pathway. PDE9i did not affect any of these disease-related pathways. Two dosages of the PDE9 inhibitor BAY 73-6691 known to be effective in other rat models have only limited cardio-renal protective effects in 5/6 nephrectomized rats.

Dynamics of Endothelial Cell Generation and Turnover in Arteries During Homeostasis and Diseases.

BACKGROUND: Endothelial cell (EC) generation and turnover by self-proliferation contributes to vascular repair and regeneration. The ability to accurately measure the dynamics of EC generation would advance our understanding of cellular mechanisms of vascular homeostasis and diseases. However, it is currently challenging to evaluate the dynamics of EC generation in large vessels such as arteries because of their infrequent proliferation. METHODS: By using dual recombination systems based on Cre-loxP and Dre-rox, we developed a genetic system for temporally seamless recording of EC proliferation in vivo. We combined genetic recording of EC proliferation with single-cell RNA sequencing and gene knockout to uncover cellular and molecular mechanisms underlying EC generation in arteries during homeostasis and disease. RESULTS: Genetic proliferation tracing reveals that ≈3% of aortic ECs undergo proliferation per month in adult mice during homeostasis. The orientation of aortic EC division is generally parallel to blood flow in the aorta, which is regulated by the mechanosensing protein Piezo1. Single-cell RNA sequencing analysis reveals 4 heterogeneous aortic EC subpopulations with distinct proliferative activity. EC cluster 1 exhibits transit-amplifying cell features with preferential proliferative capacity and enriched expression of stem cell markers such as Sca1 and Sox18. EC proliferation increases in hypertension but decreases in type 2 diabetes, coinciding with changes in the extent of EC cluster 1 proliferation. Combined gene knockout and proliferation tracing reveals that Hippo/vascular endothelial growth factor receptor 2 signaling pathways regulate EC proliferation in large vessels. CONCLUSIONS: Genetic proliferation tracing quantitatively delineates the dynamics of EC generation and turnover, as well as EC division orientation, in large vessels during homeostasis and disease. An EC subpopulation in the aorta exhibits more robust cell proliferation during homeostasis and type 2 diabetes, identifying it as a potential therapeutic target for vascular repair and regeneration.

Allicin promotes functional recovery in ischemic stroke via glutathione peroxidase-1 activation of Src-Akt-Erk.

Allicin exhibits various pharmacological activities and has been suggested to be beneficial in the treatment of stroke. However, the underlying mechanisms are largely unknown. Here, we confirmed that allicin protected the brain from cerebral injury, which could be ascribed to its anti­apoptotic and anti­inflammatory effects, as well as the regulation of lipid metabolism, using proteomics and metabolomics analysis. Our results suggested that allicin could significantly ameliorate behavioral characteristics, cerebral infarct area, cell apoptosis, inflammatory factors, and lipid metabolic-related factors (arachidonic acid, 15-hydroperoxy-eicosatetraenoic acid (15S-HPETE), palmitoylcarnitine, and acylcarnitine) by recalibrating astrocyte homeostasis in mice with photothrombotic stroke (PT). In astrocytes, allicin significantly increased glutathione peroxidase 1 (GPX1) levels and inhibited the arachidonic acid-related pathway, which was also observed in the brains of mice with PT. Allicin was proven to inhibit hypoxia-induced astrocyte apoptosis by increasing GPX1 expression, activating proto-oncogene tyrosine-protein kinase Src (Src)- protein kinase B (AKT)-extracellular signal-regulated kinase (ERK) phosphorylation, and decreasing lipid peroxidation. Thus, we concluded that allicin significantly prevented and ameliorated ischemic stroke by increasing GPX1 levels to complete the complex physiological process.

Post-procedural and long-term functional outcomes of jailed side branches in stented coronary bifurcation lesions assessed with side branch Murray law-based quantitative flow ratio.

Introduction: In coronary bifurcation lesions treated with percutaneous coronary intervention (PCI) using a 1-stent strategy, the occurrence of side branch (SB) compromise may lead to long-term myocardial ischemia in the SB territory. Murray law-based quantitative flow ratio (µQFR) is a novel angiography-based approach estimating fractional flow reserve from a single angiographic view, and thus is more feasible to assess SB compromise in routine practice. However, its association with long-term SB coronary blood flow remains unknown. Methods: A total of 146 patients with 313 non-left main bifurcation lesions receiving 1-stent strategy with drug-eluting stents was included in this retrospective study. These lesions had post-procedural Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 in SBs, and documented angiographic images of index procedure and 6- to 24-month angiographic follow-up. Post-procedural SB µQFR was calculated. Long-term SB coronary blood flow was quantified with the TIMI grading system using angiograms acquired at angiographic follow-up. Results: At follow-up, 8 (2.6%), 16 (5.1%), 61 (19.5%), and 228 (72.8%) SBs had a TIMI flow grade of 0, 1, 2, and 3, respectively. The incidences of long-term SB TIMI flow grade ≤1 and ≤2 both tended to decrease across the tertiles of post-procedural SB µQFR. The receiver operating characteristic curve analyses indicated the post-procedural SB µQFR ≤0.77 was the optimal cut-off value to identify long-term SB TIMI flow grade ≤1 (specificity, 37.50%; sensitivity, 87.20%; area under the curve, 0.6673; P = 0.0064), and it was independently associated with 2.57-fold increased risk (adjusted OR, 2.57; 95% CI, 1.02-7.25; P = 0.045) in long-term SB TIMI flow grade ≤1 after adjustment. Discussion: Post-procedural SB µQFR was independently associated with increased risk in impaired SB TIMI flow at long-term follow-up. Further investigations should focus on whether PCI optimization based on µQFR may contribute to improve SB flow in the long term.

Left atrial appendage angiography for stroke risk prediction in patients with atrial fibrillation.

BACKGROUND: The current risk stratification schemes for stroke in patients with atrial fibrillation (AF) are insufficient for an accurate assessment of stroke risk. AIMS: This study evaluates the association between the mechanical function of the left atrial appendage (LAA), as assessed by angiography, and the risk of stroke. METHODS: We conducted a cross-sectional study to assess the mechanical function of the LAA by measuring the left atrial appendage ejection fraction (LAAEF) and grading the contrast retention (CR) using angiography. RESULTS: A total of 746 patients referred for a left atrial appendage occlusion (LAAO) procedure with (n=151; stroke group) or without (n=595; control group) a history of stroke were included in the analysis. LAAEF was significantly lower (14% [9-19] vs 20% [12-33]; p<0.001) and grade 3 CR was more common (66.9% vs 33.9%; p<0.001) in patients with a history of stroke. Multivariable analysis showed that CR was independently associated with stroke in patients with AF (grade 2 vs grade 1=7.29; 95% confidence interval [CI]: 2.84-21.65; p<0.001; grade 3 vs grade 1=16.45; 95% CI: 6.16-51.02; p<0.001). The receiver operating characteristics curve demonstrated that CR identified patients with stroke more accurately than the CHA2D-VASc score (C-statistic 0.712 vs 0.512; p<0.001), and the combination of CR and the CHA2DS2-VASc score provided the best performance (C-statistic 0.871 vs 0.829 [CHA2DS2-VASc score alone]; p=0.048) Conclusions: Impaired mechanical function of the LAA, indicated by a low LAAEF and CR, is associated with a history of stroke in patients with AF. Assessment of CR using LAA angiography helps improve the stratification scheme for stroke risk prediction.

Reno- and cardioprotective molecular mechanisms of SGLT2 inhibitors beyond glycemic control: from bedside to bench.

Large placebo-controlled clinical trials have shown that sodium-glucose cotransporter-2 inhibitors (SGLT2i) delay the deterioration of renal function and reduce cardiovascular events in a glucose-independent manner, thereby ultimately reducing mortality in patients with chronic kidney disease (CKD) and/or heart failure. These existing clinical data stimulated preclinical studies aiming to understand the observed clinical effects. In animal models, it was shown that the beneficial effect of SGLT2i on the tubuloglomerular feedback (TGF) improves glomerular pressure and reduces tubular workload by improving renal hemodynamics, which appears to be dependent on salt intake. High salt intake might blunt the SGLT2i effects on the TGF. Beyond the salt-dependent effects of SGLT2i on renal hemodynamics, SGLT2i inhibited several key aspects of macrophage-mediated renal inflammation and fibrosis, including inhibiting the differentiation of monocytes to macrophages, promoting the polarization of macrophages from a proinflammatory M1 phenotype to an anti-inflammatory M2 phenotype, and suppressing the activation of inflammasomes and major proinflammatory factors. As macrophages are also important cells mediating atherosclerosis and myocardial remodeling after injury, the inhibitory effects of SGLT2i on macrophage differentiation and inflammatory responses may also play a role in stabilizing atherosclerotic plaques and ameliorating myocardial inflammation and fibrosis. Recent studies suggest that SGLT2i may also act directly on the Na+/H+ exchanger and Late-INa in cardiomyocytes thus reducing Na+ and Ca2+ overload-mediated myocardial damage. In addition, the renal-cardioprotective mechanisms of SGLT2i include systemic effects on the sympathetic nervous system, blood volume, salt excretion, and energy metabolism.

Accuracy and limitation of plaque detection by coronary CTA: a section-to-section comparison with optical coherence tomography.

Plaques identified by Coronary CT angiography (CCTA) are important in clinical diagnosis and primary prevention. High-risk plaque features by CCTA have been extensively validated using optical coherence tomography (OCT). However, since their general diagnostic performance and limitations have not been fully investigated, we sought to compare CCTA with OCT among consecutive vessel sections. We retrospectively compared 188 consecutive plaques and 84 normal sections in 41 vessels from 40 consecutive patients referred for chest pain evaluation who had both CCTA and OCT with a median time lapse of 1 day. The distance to reference points were used to co-register between the modalities and the diagnostic performance of CCTA was evaluated against OCT. Plaque categories evaluated by CT were calcified, non-calcified and mixed. The diagnostic performance of CCTA was excellent for detecting any plaque identified by OCT with the sensitivity, specificity, negative and positive predictive values and accuracy of 92%, 98%, 99%, 84% and 93%, respectively. The lower than expected negative predictive value was due to failure of detecting sub-millimeter calcified (≤ 0.25 mm2) (N = 12) and non-calcified plaques (N = 4). Misclassification of plaque type accounted for majority of false negative findings (25/41, 61%) which was most prevalent among the mixed plaque (19/41, 46%). There was calcification within mixed plaques (N = 5) seen by CCTA but missed by OCT. Our findings suggest that CCTA is excellent at identifying coronary plaques except those sub-millimeter in size which likely represent very early atherosclerosis, although the clinical implication of very mild atherosclerosis is yet to be determined.

Transient Receptor Vanilloid Subtype 4-Mediated Ca2+ Influx Promotes Glomerular Endothelial Inflammation in Sepsis-Associated Acute Kidney Injury.

Sepsis-associated acute kidney injury (S-AKI) is a frequent complication in patients who are critically ill, which is often initiated by glomerular endothelial cell dysfunction. Although transient receptor vanilloid subtype 4 (TRPV4) ion channels are known to be permeable to Ca2+ and are widely expressed in the kidneys, the role of TRPV4 on glomerular endothelial inflammation in sepsis remains elusive. In the present study, we found that TRPV4 expression in mouse glomerular endothelial cells (MGECs) increased after lipopolysaccharide (LPS) stimulation or cecal ligation and puncture challenge, which increased intracellular Ca2+ in MGECs. Furthermore, the inhibition or knockdown of TRPV4 suppressed LPS-induced phosphorylation and translocation of inflammatory transcription factors NF-κB and IRF-3 in MGECs. Clamping intracellular Ca2+ mimicked LPS-induced responses observed in the absence of TRPV4. In vivo experiments showed that the pharmacologic blockade or knockdown of TRPV4 reduced glomerular endothelial inflammatory responses, increased survival rate, and improved renal function in cecal ligation and puncture-induced sepsis without altering renal cortical blood perfusion. Taken together, our results suggest that TRPV4 promotes glomerular endothelial inflammation in S-AKI and that its inhibition or knockdown alleviates glomerular endothelial inflammation by reducing Ca2+ overload and NF-κB/IRF-3 activation. These findings provide insights that may aid in the development of novel pharmacologic strategies for the treatment of S-AKI.

Renoprotective effects of empagliflozin are linked to activation of the tubuloglomerular feedback mechanism and blunting of the complement system.

The mechanisms of nephroprotection in nondiabetic chronic kidney disease (CKD) models by sodium-glucose cotransporter 2 (SGLT2) inhibitors are not well defined. Five groups were established: sham-operated rats, placebo-treated rats with 5/6 nephrectomy (5/6Nx), 5/6Nx + telmisartan (5 mg/kg/day), 5/6Nx + empagliflozin (3 mg/kg/day), and 5/6Nx + empagliflozin (15 mg/kg/day). Treatment duration was 95 days. Empagliflozin showed a dose-dependent beneficial effect on the change from baseline of creatinine clearance (Ccr). The urinary albumin-to-creatinine ratio likewise improved in a dose-dependent manner. Both dosages of empagliflozin improved morphological kidney damage parameters such as renal interstitial fibrosis and glomerulosclerosis. 5/6 nephrectomy led to a substantial reduction of urinary adenosine excretion, a surrogate parameter of the tubuloglomerular feedback (TGF) mechanism. Empagliflozin caused a dose-dependent increase in urinary adenosine excretion. The urinary adenosine excretion was negatively correlated with renal interstitial fibrosis and positively correlated with Ccr. Immunofluorescence analysis revealed that empagliflozin had no effect on CD8+ and CD4+ T cells as well as on CD68+ cells (macrophages). To further explore potential mechanisms, a nonhypothesis-driven approach was used. RNA sequencing followed by quantitative real-time polymerase chain reaction revealed that complement component 1Q subcomponent A chain (C1QA) as well as complement component 1Q subcomponent C chain (C1QC) gene expression were upregulated in the placebo-treated 5/6Nx rats and this upregulation was blunted by treatment with empagliflozin. In conclusion, empagliflozin-mediated nephroprotection in nondiabetic CKD is due to a dose-dependent activation of the TGF as well as empagliflozin-mediated effects on the complement system.

Outcomes of atrial septostomy and effect on long-term survival in patients with idiopathic pulmonary arterial hypertension: A single-center cohort.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a chronic progressive disease that may lead to right heart failure (RHF) and early death. Balloon atrial septostomy (BAS) may be used for the palliative treatment of RHF from PAH. We present our contemporary institutional experience of utilizing BAS in idiopathic PAH (IPAH) patients with refractory RHF to investigate the effect on the safety, efficacy and long-term survival. METHODS: This retrospective analysis included 12 IPAH patients with severe RHF from March 2017 to May 2019 who were assessed as high risk. All patients received standard treatment including combination of PAH-specific drugs. Graded BAS was performed on these patients due to unsatisfactory clinical response. Clinical, functional and hemodynamic variables before and immediately after the procedure were collected. 1-year follow-up outcomes and 3-year survival rate were further analyzed. RESULTS: Successful septostomy was achieved in cases with no procedure-related complications. All patients obtained hemodynamic improvement immediately after the procedure. The WHO functional class and exercise endurance improved at 1-year follow-up, 7 of 12 patients achieved intermediate-low risk status, while the rest remained at intermediate-high risk. 2 patients died at 18 and 20 months due to malignant arrhythmia and advanced heart failure, respectively. Survival at 1 year and 3 years was 100% and 83.3%. CONCLUSIONS: In selected IPAH patients with refractory RHF, BAS is an additional therapeutic strategy, especially when PAH-specific drugs could not achieve the treatment target. BAS can improve hemodynamic variables, bring clinical and cardiac functional benefits and increase the 3-year survival.

Jujuboside A attenuates sepsis-induced cardiomyopathy by inhibiting inflammation and regulating autophagy.

BACKGROUND: Jujuboside A (JuA), as a main effective component of Jujubogenin, has long been known as a sedative-hypnotic drug. The aim of the current study was to investigate the potential effect of JuA on sepsis-induced cardiomyopathy (SIC) induced by lipopolysaccharide (LPS). METHOD: Wide type C57BL/6 mice and neonatal rat cardiomyocytes (NRCMs) were exposed to LPS to establish myocardial toxicity models. Cardiac function of septic mice was detected by echocardiography. Moreover, the survival rate was calculated for 7 days. ELISA assays were used to analyze inflammatory factors in serum. Furthermore, western blotting, flow cytometry and TUNEL staining were performed to assess cell apoptosis and transmission electron microscopy detect the number of autophagosomes in myocardium. Finally, the expression of proteins related to pyroptosis, autophagy and oxidative stress was analyzed by western blotting and immunohistochemistry staining. RESULTS: Results showed that JuA pretreatment significantly improved the survival rate and cardiac function, and suppressed systemic inflammatory response in septic mice. Further study revealed that JuA could decrease cell apoptosis and pyroptosis; instead, it strengthened autophagy in SIC. Moreover, JuA also significantly decreased oxidative stress and nitrodative stress, as evidenced by suppressing the superoxide production and downregulating iNOS and gp91 expression in vivo. In addition, the autophagy inhibitor 3-MA significantly abolished the effect of JuA on autophagic activity in SIC. CONCLUSION: In conclusion, the findings indicated that JuA attenuates cardiac function via blocking inflammasome-mediated apoptosis and pyroptosis, at the same time by enhancing autophagy in SIC, heralding JuA as a potential therapy for sepsis.

SENP2 Promotes VSMC Phenotypic Switching via Myocardin De-SUMOylation.

Myocardin is a master regulator of smooth muscle cell (SMC) differentiation, which induces the expression of smooth-muscle-specific genes through its direct association with serum response factor (SRF). During the past two decades, significant insights have been obtained regarding the regulatory control of myocardin expression and transcriptional activity at the transcriptional, post-transcriptional, and post-translational levels. However, whether and how SUMOylation plays important roles in modulating myocardin function remain elusive. In this study, we found that myocardin is modified by SUMO-1 at lysine 573, which can be reversibly de-conjugated by SENP2. SUMO-1 modification promotes myocardin protein stability, whereas SENP2 facilitates its proteasome-dependent degradation. Moreover, we found that PIAS4 is the SUMO E3 ligase that enhances the SUMOylation and protein stability of myocardin. Most importantly, we found that SENP2 promotes phenotypic switching of VSMC. We therefore concluded that SENP2 promotes VSMC phenotypic switching via de-SUMOylation of myocardin and regulation of its protein stability.

L-shaped association of serum 25-hydroxyvitamin D concentrations with cardiovascular and all-cause mortality in individuals with osteoarthritis: results from the NHANES database prospective cohort study.

BACKGROUND: The relationship between vitamin D status and mortality in patients with osteoarthritis (OA) is unknown. This study investigated the associations of serum 25-hydroxyvitamin D [25(OH)D] concentrations with all-cause and cause-specific mortality among American adults with OA. METHODS: This study included 2556 adults with OA from the National Health and Nutrition Examination Survey (2001-2014). Death outcomes were ascertained by linkage to National Death Index (NDI) records through 31 December 2015. Cox proportional hazards model and two-piecewise Cox proportional hazards model were used to elucidate the nonlinear relationship between serum 25(OH)D concentrations and mortality in OA patients, and stratified analyses were performed to identify patients with higher mortality risk. RESULTS: During 16,606 person-years of follow-up, 438 all-cause deaths occurred, including 74 cardiovascular disease (CVD)-related and 78 cancer deaths. After multivariable adjustment, lower serum 25(OH)D levels were significantly and nonlinearly associated with higher risks of all-cause and CVD mortality among participants with OA. Furthermore, we discovered L-shaped associations between serum 25(OH)D levels and all-cause and CVD mortality, with mortality plateauing at 54.40 nmol/L for all-cause mortality and 27.70 nmol/L for CVD mortality. Compared to participants with 25(OH)D levels below the inflection points, those with higher levels had a 2% lower risk for all-cause mortality (hazard ratio [HR] 0.98, 95% confidence interval [CI] 0.96-0.99) and 17% lower risk for CVD mortality (HR 0.83, 95% CI 0.72-0.95). CONCLUSIONS: Nonlinear associations of serum 25(OH)D levels with all-cause and CVD mortality were observed in American patients with OA. The thresholds of 27.70 and 54.40 nmol/L for CVD and all-cause mortality, respectively, may represent intervention targets for lowering the risk of premature death and cardiovascular disease, but this needs to be confirmed in large clinical trials.

Alprostadil vs. isosorbide dinitrate in ameliorating angina episodes in patients with coronary slow flow phenomenon: A randomized controlled trial.

Background: The optimum therapy for coronary slow flow phenomenon (CSFP) stays debatable. This study compared the effectiveness of alprostadil with isosorbide dinitrate in alleviating angina episodes in CSFP patients. Methods: In this prospective, randomized controlled study, 102 patients with CSFP without severe coronary artery stenosis that exhibited stable angina were allocated randomly in a ratio of 1:1 to either the alprostadil group (40 µg, three times per day, n = 51) or the isosorbide dinitrate group (5 mg, three times per day, n = 51). Frequency of angina events, intensity of suffering, and the Canadian Cardiovascular Society (CCS) grading of angina pectoris were evaluated at baseline and one month after. Additionally, the Seattle Angina Questionnaire (SAQ) was assessed. Results: Baseline characteristics were comparable between the two groups. At 1-month follow-up, patients administered with alprostadil experienced fewer angina episodes [episodes per week, 1 (2) vs. 2 (2), P < 0.001] and less pain intensity [self-evaluated pain score, 2 (3) vs. 3 (4), P < 0.001] than those with isosorbide dinitrate. In the alprostadil group, 78.4% of patients were classified as CCS class I, significantly higher than the 47.1% seen in the isosorbide dinitrate group (P = 0.001). Furthermore, treatment of alprostadil led to a significant improvement in the SAQ score (7.09 U, 95% CI: 4.22-9.96, P < 0.001) compared to isosorbide dinitrate. Additionally, fewer patients suffered headaches when receiving alprostadil (7.8% vs. 19.6%, P = 0.084). Conclusion: Alprostadil was more effective in ameliorating angina symptoms in CSFP patients than isosorbide dinitrate. Clinical trial registration: [www.chictr.org.cn], identifier [ChiCTR2000033233].

Angiotensin II Promotes White Adipose Tissue Browning and Lipolysis in Mice.

Emerging evidence has revealed that all components of the renin-angiotensin system (RAS) are present in adipose tissue. Angiotensin II (Ang II), the major bioactive component of the RAS, has been recognized as an adipokine involved in regulating energy homeostasis. However, the precise role of Ang II in white adipose tissue (WAT) remodeling remains to be elucidated. In this present study, C57BL/C male mice were continuously infused with different doses of Ang II (1.44 mg/kg/d or 2.5 mg/kg/d) or saline for 2 weeks and treated with or without the Ang II type 1 receptor blocker valsartan. H&E staining and immunohistochemistry were conducted to investigate the white-to-brown fat conversion. The level of serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) was measured. RNA sequencing was employed to explore the differentially expressed genes and their enriched pathways between control and Ang II groups. Our results showed that Ang II substantially resulted in loss of body weight and fat mass. Most importantly, Ang II treatment induced WAT browning in mice, which was partially attenuated by valsartan treatment. Furthermore, Ang II perturbed the serum lipid profiles. Ang II treatment elevated serum levels of TC, TG, LDL-C, and HDL-C in mice. Mechanistically, thermogenesis, cell respiration, and lipid metabolism-associated mRNAs showed significantly increased expression profiling in Ang II-treated WATs compared with control WATs. Moreover, we found that Ang II treatment enhanced AMPK phosphorylation in adipocytes. Therefore, Ang II promotes WAT browning and lipolysis via activating the AMPK signaling pathway.

Exercise-derived peptide protects against pathological cardiac remodeling.

BACKGROUND: Exercise training protects the heart against pathological cardiac remodeling and confers cardioprotection from heart failure. However, the underlying mechanism is still elusive. METHODS: An integrative analysis of multi-omics data of the skeletal muscle in response to exercise is performed to search for potential exerkine. Then, CCDC80tide is examined in humans after acute exercise. The role of CCDC80tide is assessed in a mouse model of hypertensive cardiac remodeling and in hypertension-mediated cell injury models. The transcriptomic analysis and immunoprecipitation assay are conducted to explore the mechanism. FINDINGS: The coiled-coil domain-containing protein 80 (CCDC80) is found strongly positively associated with exercise. Interestingly, exercise stimuli induce the secretion of C-terminal CCDC80 (referred as CCDC80tide hereafter) via EVs-encapsulated CCDC80tide into the circulation. Importantly, cardiac-specific expression of CCDC80tide protects against angiotensin II (Ang II)-induced cardiac hypertrophy and fibrosis in mice. In in vitro studies, the expression of CCDC80tide reduces Ang II-induced cardiomyocyte hypertrophy, cardiac microvascular endothelial cell (CMEC) inflammation, and mitigated vascular smooth muscle cell (VSMC) proliferation and collagen formation. To understand the cardioprotective effect of CCDC80tide, a transcriptomic analysis reveals a dramatic inhibition of the STAT3 (Signal transducer and activator of transcription 3) signaling pathway in CCDC80tide overexpressing cells. Mechanistically, CCDC80tide selectively interacts with the kinase-active form of JAK2 (Janus kinase 2) and consequently inhibits its kinase activity to phosphorylate and activate STAT3. INTERPRETATION: The results provide new insights into exercise-afforded cardioprotection in pathological cardiac remodeling and highlight the therapeutic potential of CCDC80tide in heart failure treatment. FUNDING: This work was supported by the National Natural Science Foundation of China [Grant/Award Numbers: 81770428, 81830010, 82130012, 81900438, 82100447); Shanghai Science and Technology Committee [Grant/Award Numbers: 21S11903000, 19JC1415702]; Emerging and Advanced Technology Programs of Hospital Development Center of Shanghai [Grant/Award Number: SHDC12018129]; China Postdoctoral Science Foundation [2021M692108]; and China National Postdoctoral Program for Innovative Talents [BX20200211].

Nongated Computed Tomography Predicts Perioperative Cardiovascular Risk in Lung Cancer Surgery.

BACKGROUND: The coronary artery calcification score (CACS), a strong predictor of cardiovascular events and mortality, can be assessed by nongated chest computed tomography (CT). The study aimed to determine whether CACS based on nongated CT is predictive of perioperative cardiovascular events during intermediate-risk lung cancer surgery. METHODS: In this retrospective, single-center study, we used nongated CT images to evaluate CACS in 4491 patients with lung cancer who underwent intermediate-risk surgeries. Perioperative cardiovascular events were defined as in-hospital cardiac death, nonfatal myocardial infarction, heart failure, atrial and ventricular arrhythmia with hemodynamic compromise, and complete heart block. Risk factors of perioperative cardiovascular events were identified by multivariate logistic regression analysis. RESULTS: In total, 110 inpatients (2.5%) experienced perioperative cardiac events. Coronary calcification was observed on nongated CT in 1070 (23.8%) patients. CACS was significantly associated with the incidence of cardiovascular events and longer hospital stays. According to receiver operating characteristic curve analysis, the CACS cutoff value was set to 1. In the multivariate analysis, CACS ≥1 (odds ratio, 1.75; 95% CI, 1.14-2.68; P = .011) or the number of calcified vessels (odds ratio, 1.23; 95% CI, 1.01-1.50; P = .043), age, forced expiratory volume in 1 second/predicted, operation time, and thoracotomy were predictive of cardiovascular complications. CONCLUSIONS: CACS is an independent predictor of severe perioperative cardiovascular risk in patients undergoing intermediate-risk lung cancer surgery. CACS may represent a valuable tool for preoperative risk assessment of these patients.

Nur77 Deficiency Exacerbates Macrophage NLRP3 Inflammasome-Mediated Inflammation and Accelerates Atherosclerosis.

Purpose: Activation of NLR (nucleotide-binding and leucine-rich repeat immune receptor) family pyrin domain containing 3 (NLRP3) inflammasome mediating interleukin- (IL-) 1ß secretion has emerged as an important component of inflammatory processes in atherogenesis. The nuclear receptor Nur77 is highly expressed in human atherosclerotic lesions; however, its functional role in macrophage NLRP3 inflammasome activation has not yet been clarified. Methods, Materials, and Results. Eight-week-old apolipoprotein E (ApoE)-/- and ApoE-/- Nur77-/- mice that were fed a Western diet underwent partial ligation of the left common carotid artery (LCCA) and left renal artery (LRA) to induce atherogenesis. Four weeks later, severe plaque burden associated with increased lipid deposition, reduced smooth muscle cells, macrophage infiltration, and decreased collagen expression was identified in ApoE-/- Nur77-/- mice compared with those in ApoE-/- mice. ApoE-/- Nur77-/- mice showed increased macrophage inflammatory responses in carotid atherosclerotic lesions. In vitro studies demonstrated that oxidized low-density lipoprotein cholesterol (ox-LDL) increased the release of lactate dehydrogenase (LDH) and upregulated the expressions of cleaved caspase-1, cleaved IL-1ß and gasdermin D (GSMD) in WT peritoneal macrophages (PMs) in a NLRP3-dependent manner. Nur77-/- PMs exhibited a further increased level of NLRP3 inflammasome-mediated inflammation under ox-LDL treatment compared with WT PMs. Mechanistically, Nur77 could bind to the promoter of NLRP3 and inhibit its transcriptional activity. Conclusions: This study demonstrated that Nur77 deletion promotes atherogenesis by exacerbating NLRP3 inflammasome-mediated inflammation.