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.

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.

Assessment of six surrogate insulin resistance indexes for predicting cardiometabolic multimorbidity incidence in Chinese middle-aged and older populations: Insights from the China health and retirement longitudinal study.

AIMS: Insulin resistance (IR) is associated with cardiometabolic multimorbidity (CMM). We aimed to explore the predictive value of six surrogate IR indexes-Chinese visceral adiposity index (CVAI), lipid accumulation product (LAP), triglyceride-glucose (TyG), atherogenic index of plasma (AIP), TyG-body mass index (TyGBMI), and TyG-waist circumference (TyGwaist)-to establish the CMM incidence in Chinese middle-aged and older populations. MATERIAL AND METHODS: To estimate the odds ratio (OR) with a 95% confidence interval (95% CI) for incident CMM using six surrogates, we analysed data from the China Health and Retirement Longitudinal Study using multivariate logistic regression models. The nonlinear dose-response correlation was evaluated using restricted cubic spline analysis; predictive performance was assessed using receiver operator characteristic curves. RESULTS: Among 6451 eligible participants, 268 (4.2%) developed CMM during the 4-year follow-up period. The ORs (95% CI) for incident CMM increased with increasing CVAI quartiles (Q) [Q2: 1.71, 1.03-2.90; Q3: 2.72, 1.70-4.52; Q4: 5.16, 3.29-8.45; all p < 0.05] after full adjustment, with Q1 as the reference. Other indexes yielded similar results. These associations remained significant in individuals with a normal body mass index. Notably, CVAI, AIP, and TyG exhibited a linear dose-response relationship with CMM (Pnonlinear ≥0.05), whereas LAP, TyGBMI, and TyGwaist displayed significant nonlinear correlations (Pnonlinear <0.05). The area under the curve for the CVAI (0.691) was significantly superior to that of other indexes (all p < 0.05). CONCLUSIONS: The six IR surrogates were independently associated with CMM incidence. CVAI may be the most appropriate indicator for predicting CMM in middle-aged and older Chinese populations.

Genetic Lineage Tracing of Pericardial Cavity Macrophages in the Injured Heart.

BACKGROUND: Macrophages play an important role in cardiac repair after myocardial infarction (MI). In addition to the resident macrophages and blood-derived monocytes, Gata6+ cavity macrophages located in the pericardial space were recently reported to relocate to the injured myocardium and prevent cardiac fibrosis. However, there is no direct genetic evidence to support it. METHODS: We used dual recombinases (Cre and Dre) to specifically label Gata6+ pericardial macrophages (GPCMs) in vivo. For functional study, we generated genetic systems to specifically ablate GPCMs by induced expression of DTR (diphtheria toxin receptor) or knockout of Gata6 (GATA binding protein 6) gene in GPCMs. We used these genetic systems to study GPCMs in pericardium intact MI model. RESULTS: Dual recombinases-mediated genetic system targeted GPCMs specifically and efficiently. Lineage tracing study revealed accumulation of GPCMs on the surface of MI heart without deep penetration into the myocardium. We did not detect significant change of cardiac fibrosis or function of MI hearts after cell ablation or Gata6 knockout in GPCMs. CONCLUSIONS: GPCMs minimally invade the injured heart after MI. Nor do they prevent cardiac fibrosis and exhibit reparative function on injured heart. This study also underlines the importance of using specific genetic tool for studying in vivo cell fates and functions.

Insight into endothelial cell-derived extracellular vesicles in cardiovascular disease: Molecular mechanisms and clinical implications.

The endothelium is crucial in regulating vascular function. Extracellular vesicles (EVs) serve as membranous structures released by cells to facilitate intercellular communication through the delivery of nucleic acids, lipids, and proteins to recipient cells in an paracrine or endocrine manner. Endothelial cell-derived EVs (EndoEVs) have been identified as both biomarkers and significant contributors to the occurrence and progression of cardiovascular disease (CVD). The impact of EndoEVs on CVD is complex and contingent upon the condition of donor cells, the molecular cargo within EVs, and the characteristics of recipient cells. Consequently, elucidating the underlying molecular mechanisms of EndoEVs is crucial for comprehending their contributions to CVD. Moreover, a thorough understanding of the composition and function of EndoEVs is imperative for their potential clinical utility. This review aims provide an up-to-date overview of EndoEVs in the context of physiology and pathophysiology, as well as to discuss their prospective clinical applications.

The survival benefit of metastasectomy for metastatic non-clear cell renal cell carcinoma: a retrospective cohort study.

PURPOSE: The aim of this study was to explore the benefit the metastasectomy for patients with metastatic non-clear cell carcinoma (non-ccRCC). METHODS: This study enrolled 120 patients with confirmed metastatic non-ccRCC from the RCC database of our center from 2008 to 2021. Patients without metastasectomy were grouped as radical nephrectomy without metastasectomy patients. The clinical outcomes included overall survival (OS) and progression-free survival (PFS). Cox regression and Kaplan-Meier analyses were used to assess potential factors that predict clinical benefits from metastasectomy. RESULTS: A total of 100 patients received radical nephrectomy alone, while the remaining 20 patients underwent both radical nephrectomy and metastasectomy. There was no significant difference in age between the two groups. Out of 100 patients who underwent radical nephrectomy, 60 were male, and out of 20 patients who had both radical nephrectomy and metastasectomy, 12 were male. Patients who underwent systemic therapy plus radical nephrectomy and metastasectomy had significantly better PFS (27.1 vs. 14.0, p = 0.032) and OS (67.3 vs. 24.0, p = 0.043) than those who underwent systemic therapy plus radical nephrectomy alone. Furthermore, for patients without liver metastasis (n = 54), systemic therapy plus radical nephrectomy and metastasectomy improved both PFS (p = 0.028) and OS (p = 0.043). Similarly, for patients with metachronous metastasis, systemic therapy plus radical nephrectomy and metastasectomy improved both PFS (p = 0.043) and OS (p = 0.032). None of the patients experienced serious perioperative complications (Clavien-Dindo Classification ≥ III grade). CONCLUSION: Metastasectomy in patients with metastatic non-ccRCC may provide clinical benefits in terms of improved PFS and OS, especially in patients without liver metastasis and those with metachronous metastasis.

Myeloid SENP3 deficiency protects mice from diet and age-induced obesity via regulation of YAP1 SUMOylation.

Obesity is characterized by chronic low-grade inflammation, which is driven by macrophage infiltration in adipose tissue and leads to elevated cytokines such as interleukin-1ß (IL-1ß) in the circulation and tissues. Previous studies demonstrate that SENP3, a redox-sensitive SUMO2/3-specific protease, is strongly implicated in the development and progression of cancer and cardiovascular diseases. However, the role of SENP3 in obesity-associated inflammation remains largely unknown. To better understand the effects of SENP3 on adipose tissue macrophage (ATM) activation and function within the context of obesity, we generated mice with myeloid-specific deletion of SENP3 (Senp3flox/flox;Lyz2-Cre mice). We found that the expression of SENP3 is dramatically increased in ATMs during high-fat diet (HFD)-induced obesity in mice. Senp3flox/flox;Lyz2-Cre mice show lower body weight gain and reduced adiposity and adipocyte size after challenged with HFD and during aging. Myeloid-specific SENP3 deletion attenuates macrophage infiltration in adipose tissue and reduces serum levels of inflammatory factors during diet and age-induced obesity. Furthermore, we found that SENP3 knockout markedly inhibits cytokine release from macrophage after lipopolysaccharide and palmitic acid treatment in vitro. Mechanistically, in cultured peritoneal macrophages, SENP3 protein level is enhanced by IL-1ß, in parallel with the upregulation of Yes-associated protein 1 (YAP1). Moreover, we demonstrated that SENP3 modulates de-SUMO modification of YAP1 and SENP3 deletion abolishes the upregulation of YAP1 induced by IL-1ß. Most importantly, SENP3 deficiency reduces YAP1 protein level in adipose tissue during obesity. Our results highlight the important role of SENP3 in ATM inflammation and diet and age-induced obesity.

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.

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.

Impact of Low Voltage Threshold Adjustment on Activation Mapping Interpretation for Atrial Tachycardia in Low-Voltage Left Atrium.

Background: The misinterpretation of activation propagation within low voltage zone (LVZ) can complicate atrial tachycardia (AT) mechanism analysis, especially in patients with remodeled atrial substrate. This study investigated the impact of low voltage threshold adjustment (LVTA) on left atrial (LA) tachycardia activation mapping interpretation. Methods: We identified 55 ATs in 42 patients undergoing catheter ablation for LA tachycardia, with a mean LA voltage of < 0.5 mV. Activation mapping of LA or both atria was used to evaluate AT mechanisms before and after LVTA. Patients underwent regular clinic follow-up after the procedure. Results: Comparing activation mapping before and after LVTA revealed four categories: (1) complete change in AT circuit and ablation design in 9 ATs; (2) an unchanged AT circuit but tailored ablation design in 16 ATs; (3) identification of bystander gaps in 3 ATs; (4) an unchanged AT circuit and ablation design in 27 ATs. Effective ablation, defined as AT termination or circuit change, was obtained in all 9 Type 1 ATs and 15 of 16 Type 2 ATs by targeting the critical area identified by activation mapping after LVTA. After a median follow-up of 16.5 months, the cumulative freedom from AT was 69.3%. Conclusions: In patients with low LA voltage, conduction propagation hidden within LVZ was not uncommon, but is often excluded from activation mapping. LVTA can uncover this subtle conduction propagation with reliable accuracy, improving the veracity of activation mapping, and helping guide subsequent ablation.

An Integrated Algorithm for Differentiating Hypertrophic Cardiomyopathy From Hypertensive Heart Disease.

BACKGROUND: Differentiating hypertrophic cardiomyopathy (HCM) from hypertensive heart disease (HHD) is challenging. PURPOSE: To identify differences between HCM and HHD on a patient basis using MRI. STUDY TYPE: Retrospective. POPULATION: A total of 219 subjects, 148 in phase I (baseline data and algorithm development: 75 HCM, 33 HHD, and 40 controls) and 71 in phase II (algorithm validation: 56 HCM and 15 HHD). FIELD STRENGTH/SEQUENCE: Contrast-enhanced inversion-prepared gradient echo and cine-balanced steady-state free precession sequences at 3.0 T. ASSESSMENT: MRI parameters assessed included left ventricular (LV) ejection fraction (LVEF), LV end systolic and end diastolic volumes (LVESV and LVEDV), mean maximum LV wall thickness (MLVWT), LV global longitudinal and circumferential strain (GRS, GLS, and GCS), and native T1. Parameters, which were significantly different between HCM and HHD in univariable analysis, were entered into a principal component analysis (PCA). The selected components were then introduced into a multivariable regression analysis to model an integrated algorithm (IntA) for screening the two disorders. IntA performance was assessed for patients with and without LGE in phase I (development) and phase II (validation). STATISTICAL TESTS: Univariable regression, PCA, receiver operating curve (ROC) analysis. A P value <0.05 was considered statistically significant. RESULTS: Derived IntA formulation included LVEF, LVESV, LVEDV, MLVWT, and GCS. In LGE-positive subjects in phase l, the cutoff point of IntA ≥81 indicated HCM (83% sensitivity and 91% specificity), with the area under the ROC curve (AUC) of 0.900. In LGE-negative subjects, a higher possibility of HCM was indicated by a cutoff point of IntA ≥84 (100% sensitivity and 82% specificity), with an AUC of 0.947. Validation of IntA in phase II resulted in an AUC of 0.846 in LGE-negative subjects and 0.857 in LGE-positive subjects. DATA CONCLUSION: A per-patient-based IntA algorithm for differentiating HCM and HHD was generated from MRI data and incorporated FT, LGE and morphologic parameters. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 2.

Drug-coated balloon for the treatment of small vessel disease: 9 months of angiographic results and 12 months of clinical outcomes of the PEPCAD China SVD study.

BACKGROUND: Whether the drug-coated balloons (DCBs)-alone strategy was superior to plain old balloon angioplasty (POBA) in treating SVD remains unknown. AIMS: We aimed to evaluate the efficacy and safety of DCBs for the treatment of coronary de novo small vessel disease (SVD) and provide further evidence for extending the clinical indications of DCBs. (ChiCTR1800014966). METHODS: Eligible patients were randomized at a 2:1 ratio to receive DCB treatment or POBA in this prospective, multicenter clinical trial. The reference vessel diameter of lesions was visually assessed to be 2.0 to 2.75 mm. The primary endpoint of the study was angiographic in-segment late luminal loss (LLL) at the 9-month follow-up to demonstrate the superiority of DCB treatment to POBA in SVD. The composite clinical endpoints included clinically driven target lesion revascularization (CD-TLR), target lesion failure (TLF), major adverse cardiac events (MACEs), and thrombosis at the 12-month follow-up. RESULTS: A total of 270 patients were enrolled (181 for DCB, 89 for POBA) at 18 centers in China. The primary endpoint of 9-month in-segment LLL in the intention-to-treat population was 0.10 ± 0.33 mm with DCB and 0.25 ± 0.38 mm with POBA (p = 0.0027). This difference indicated significant superiority of DCB treatment (95% CI: -0.22, -0.04, psuperiority = 0.0068). The rates of the clinical endpoints-CD-TLR, TLF, and MACEs-were comparable between groups. No thrombosis events were reported. CONCLUSIONS: DCB treatment of de novo SVD was superior to POBA with lower 9-month in-segment LLL. The rates of clinical events were comparable between the two devices.

The protective effect of the mitochondrial-derived peptide MOTS-c on LPS-induced septic cardiomyopathy.

Septic cardiomyopathy is associated with mechanisms such as excessive inflammation, oxidative stress, regulation of calcium homeostasis, endothelial dysfunction, mitochondrial dysfunction, and cardiomyocyte death, and there is no effective treatment at present. MOTS-c is a mitochondria-derived peptide (MDP) encoded by mitochondrial DNA (mtDNA) that protects cells from stresses in an AMPK-dependent manner. In the present study, we aim to explore the protective effect of MOTS-c on lipopolysaccharide (LPS)-induced septic cardiomyopathy. LPS is used to establish a model of septic cardiomyopathy. Our results demonstrate that MOTS-c treatment reduces the mRNA levels of inflammatory cytokines ( IL-1ß, IL-4, IL-6, and TNFα) in cardiomyocytes and the levels of circulating myocardial injury markers, such as CK-MB and TnT, alleviates cardiomyocyte mitochondrial dysfunction and oxidative stress, reduces cardiomyocyte apoptosis, activates cardioprotection-related signaling pathways, including AMPK, AKT, and ERK, and inhibits the inflammation-related signaling pathways JNK and STAT3. However, treatment with the AMPK pathway inhibitor compound C (CC) abolishes the positive effect of MOTS-c on LPS stress. Collectively, our research suggests that MOTS-c may attenuate myocardial injury in septic cardiomyopathy by activating AMPK and provides a new idea for therapeutic strategies in septic cardiomyopathy.

Smooth Muscle Heterogeneity and Plasticity in Health and Aortic Aneurysmal Disease.

Vascular smooth muscle cells (VSMCs) are the predominant cell type in the medial layer of the aorta, which plays a critical role in the maintenance of aortic wall integrity. VSMCs have been suggested to have contractile and synthetic phenotypes and undergo phenotypic switching to contribute to the deteriorating aortic wall structure. Recently, the unprecedented heterogeneity and diversity of VSMCs and their complex relationship to aortic aneurysms (AAs) have been revealed by high-resolution research methods, such as lineage tracing and single-cell RNA sequencing. The aortic wall consists of VSMCs from different embryonic origins that respond unevenly to genetic defects that directly or indirectly regulate VSMC contractile phenotype. This difference predisposes to hereditary AAs in the aortic root and ascending aorta. Several VSMC phenotypes with different functions, for example, secreting VSMCs, proliferative VSMCs, mesenchymal stem cell-like VSMCs, immune-related VSMCs, proinflammatory VSMCs, senescent VSMCs, and stressed VSMCs are identified in non-hereditary AAs. The transformation of VSMCs into different phenotypes is an adaptive response to deleterious stimuli but can also trigger pathological remodeling that exacerbates the pathogenesis and development of AAs. This review is intended to contribute to the understanding of VSMC diversity in health and aneurysmal diseases. Papers that give an update on VSMC phenotype diversity in health and aneurysmal disease are summarized and recent insights on the role of VSMCs in AAs are discussed.

Ginsenoside Rb1 Improves Post-Cardiac Arrest Myocardial Stunning and Cerebral Outcomes by Regulating the Keap1/Nrf2 Pathway.

The prognosis of cardiac arrest (CA) is dismal despite the ongoing progress in cardiopulmonary resuscitation (CPR). ginsenoside Rb1 (Gn-Rb1) has been verified to be cardioprotective in cardiac remodeling and cardiac ischemia/reperfusion (I/R) injury, but its role is less known in CA. After 15 min of potassium chloride-induced CA, male C57BL/6 mice were resuscitated. Gn-Rb1 was blindly randomized to mice after 20 s of CPR. We assessed the cardiac systolic function before CA and 3 h after CPR. Mortality rates, neurological outcome, mitochondrial homeostasis, and the levels of oxidative stress were evaluated. We found that Gn-Rb1 improved the long-term survival during the post-resuscitation period but did not affect the ROSC rate. Further mechanistic investigations revealed that Gn-Rb1 ameliorated CA/CPR-induced mitochondrial destabilization and oxidative stress, partially via the activation of Keap1/Nrf2 axis. Gn-Rb1 improved the neurological outcome after resuscitation partially by balancing the oxidative stress and suppressing apoptosis. In sum, Gn-Rb1 protects against post-CA myocardial stunning and cerebral outcomes via the induction of the Nrf2 signaling pathway, which may offer a new insight into therapeutic strategies for CA.

ortho-Terphenylene Viologens with Through-Space Conjugation for Enhanced Photocatalytic Oxidative Coupling and Hydrogen Evolution.

A series of novel ortho-terphenylene viologen derivatives (o-TPV2+) with through-space conjugation (TSC) via the combination of ortho-terphenylene skeletons with viologen structure is reported. Their optoelectronic properties can be adjusted by N-arylation or N-alkylation reactions. Compared with other viologen derivatives, o-TPV2+ not only exhibits strong photoluminescence but also retards the charge recombination process and stabilizes the diradical state without forming a quinoid structure due to the special TSC effect. Based on their special redox characteristics, o-TPV2+ was applied to the photocatalytic oxidative coupling of benzylamine with 96% yield. In addition, pTA-o-TPV2+ (tethered with p-toluic acid)-modified g-C3N4 was used for visible-light-driven hydrogen production for the first time, exceeding 15 times the rate over unmodified g-C3N4.

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.

Homologous recombination deficiency (HRD) score in aggressive prostatic adenocarcinoma with or without intraductal carcinoma of the prostate (IDC-P).

BACKGROUND: Intraductal carcinoma of the prostate (IDC-P) is a subtype of prostate cancer featured by poor prognosis. Previous studies suggested IDC-P could have a potentially unstable genome. Homologous recombination deficiency (HRD) score is a result-oriented method to describe the genomic instability status. This study investigates the association of HRD scores with IDC-P and other clinicopathological factors and the prognostic implication of HRD scores in an aggressive prostate cancer cohort. METHODS: This study involved 123 PCa patients, including high-risk localized (M0) and de novo metastatic (M1) diseases. HRD score is calculated based on over 10,000 single-nucleotide polymorphisms distributed across the human genome. We explored the association between HRD scores and clinicopathological characteristics, genomic alterations, and patients' prognoses using rank-sum tests, chi-square tests, Kaplan-Meier curves, and Cox proportional hazards method. RESULTS: The median HRD score of this cohort is 21.0, with 65 (52.8%) patients showing HRD score≥21. Tumors with IDC-P displayed higher HRD scores than adenocarcinoma (P=0.002); other high HRD score-related factors included M1 (P =0.008) and high ISUP grades (4-5) (P=0.001). MYC mutations were associated with high HRD scores (P<0.001) in the total cohort. TP53 mutations (P=0.010) and HRR pathway mutations (P=0.028) corresponded to high HRD scores in IDC-P positive and non-IDC-P patients, respectively, but not vice versa. HRD scores higher than 21 indicated significantly worse survival in the total cohort. CONCLUSIONS: M1, high Gleason score, and IDC-P pathology represent higher HRD scores in PCa. Tumors with IDC-P might have different driven mechanisms for high HRD scores than non-IDC-P. HRD score displayed prognostic value in this aggressive prostate cancer cohort.

K-80003 Inhibition of Macrophage Apoptosis and Necrotic Core Development in Atherosclerotic Vulnerable Plaques.

PURPOSE: Macrophage apoptosis coupled with a defective phagocytic clearance of the apoptotic cells promotes plaque necrosis in advanced atherosclerosis, which causes acute atherothrombotic vascular disease. Nonsteroidal anti-inflammatory drug sulindac derivative K-80003 treatment was previously reported to dramatically attenuate atherosclerotic plaque progression and destabilization. However, the underlying mechanisms are not fully understood. This study aimed to determine the role of K-80003 on macrophage apoptosis and elucidate the underlying mechanism. METHODS: The mouse model of vulnerable carotid plaque in ApoE-/- mice was developed in vivo. Consequently, mice were randomly grouped into two study groups: the control group and the K-80003 group (30 mg/kg/day). Samples of carotid arteries were collected to determine atherosclerotic necrotic core area, cellular apoptosis, and oxidative stress. The effects of K-80003 on RAW264.7 macrophage apoptosis, oxidative stress, and autophagic flux were also examined in vitro. RESULTS: K-80003 significantly suppressed necrotic core formation and inhibited cellular apoptosis of vulnerable plaques. K-80003 can also inhibit 7-ketocholesterol-induced macrophage apoptosis in vitro. Furthermore, K-80003 inhibited intraplaque cellular apoptosis mainly through the suppression of oxidative stress, which is a key cause of advanced lesional macrophage apoptosis. Mechanistically, K-80003 prevented 7-ketocholesterol-induced impairment of autophagic flux in macrophages, evidenced by the decreased LC3II and SQSTM1/p62 expression, GFP-RFP-LC3 cancellation upon K-80003 treatment. CONCLUSION: Inhibition of macrophage apoptosis and necrotic core formation by autophagy-mediated reduction of oxidative stress is one mechanism of the suppression of plaque progression and destabilization by K-80003.