Citations

Modulating immune function is a critical strategy in cancer and atherosclerosis treatments. For cancer, boosting or maintaining the immune system is crucial to prevent tumor growth. However, in vascular disease, mitigating immune responses can decrease inflammation and slow atherosclerosis progression. Anti-inflammatory therapy, therefore, presents a unique dilemma for cancer survivors: while it may decrease cardiovascular risk, it might also promote cancer growth and metastasis by suppressing the immune response. Senescence presents a potentially targetable solution to this challenge; senescence increases the risk of both cancer therapy resistance and vascular disease. Exercise, notably, shows promise in delaying this premature senescence, potentially improving cancer outcomes and lowering vascular disease risk post-treatment. This review focuses on the long-term impact of cancer therapies on vascular health. We underscore the importance of modulating senescence to balance cancer treatment’s effectiveness and its vascular impact, and we emphasize investigating the role of exercise-mediated suppression of senescence in improving cancer survivorship.

AbstractBackgroundThe efficacy of Calorie Restriction (CR) in enhancing cognition, promoting healthy aging, and extending lifespan is well‐established. Yet, it remains unclear whether the apolipoprotein E (APOE) genotype, a known modifier for aging and age‐related disorders, influences the beneficial effects of CR in countering aging.MethodsTo investigate this question, we utilized humanized APOE mouse models, which express APOE2, APOE3, or APOE4 alleles systematically (refer to as E2, E3, and E4 mice). These mice were subjected to either ad libitum (AL) feeding or 30% CR feeding, starting from 12 months and continuing up to 20 months of age (N = 11‐20/ genotype /group, mixed sex). We monitored energy expenditure using the Comprehensive Laboratory Animal Monitoring System (CLAMS). Additionally, we evaluated anxiety levels and memory capabilities through various behavioral tests. Finally, we collected brain, blood, and feces samples for transcriptomic, lipidomic, and microbiomic analyses.ResultsCLAMS measurements showed that CR significantly decreased the metabolic rate in E3 and E4 mice, but not E2 mice, during the non‐feeding period of the CR group, compared to the AL group. Furthermore, CR reduced anxiety and enhanced associative memory in E3 and E4 mice relative to the AL group. Brain transcriptomics revealed that CR upregulated the cholesterol synthesis pathway, potentially improving myelination‐related pathways in E3 and E4 mice. This finding was further validated by the increased staining intensity of myelin basic protein (MBP) observed in E3 and E4 mice from an independent cohort. In contrast, these effects were not pronounced in E2 mice. Additionally, while CR’s impact on the brain lipid profile was minor across all APOE genotypes, it significantly altered blood lipid profile of E2 mice, with minimal changes observed in E3 and E4 mice. Finally, in microbiomics, CR led to notable changes in the abundance of Bifidobacterium species in E3 and E4 mice and Lactobacillus species in E2 mice.ConclusionsOur study highlights the role of APOE genotypes in modulating the diverse effects of CR on cognition, brain transcriptomics, lipid metabolism, and the microbiome, providing a crucial foundation for considering APOE genotypes in developing prevention strategies for aging and age‐related disorders.

Background: D-flow’s impact on metabolic reprogramming, particularly glycolysis, needs reevaluation due to its conflicting role in atherosclerosis. We show that d-flow reduces LATS1/2 expression, leading to both EC proliferation and senescence. However, the exact molecular mechanisms remain elusive. Methods: We utilized EC-specific Lats1 +/- /Lats2 -/- knockout (LATS1/2-EKO) mice in a partial left carotid ligation (PLCL) model under hypercholesterolemia with AAV-PCSK9 injection to mimic d-flow. Anti-CD38 antibody (Ab68) and IgG2a control were administered intraperitoneally every 5 days at a dose of 5 mg/kg starting one day before PLCL. Plaque characterization was performed using imaging mass cytometry and sequential immunofluorescence (COMET TM ), integrating spatial metabolite data from Bruker timsTOF Flex Mass Spectrometer, and spatial single-cell metabolite data via the Visiopharm platform. Results: EC LATS1/2 depletion induced a unique atherothrombosis lesion with induced EC proliferation and senescence-associated secretory phenotype (SASP). Utilizing spatial single-cell metabolomics, we cataloged 134 distinct metabolites within the ECs. Subsequent overrepresentation analysis revealed that pathways related to glutamate and the citric acid cycle were enhanced in LATS1/2-EKO mice. Specifically, CD38-dependent downregulation of the pyruvate dehydrogenase (PDH) substrate lipoamide decreased PDH enzymatic activity, linking to CD38 to senescence induction. This inhibition led to a metabolic shift towards YAP-dependent glutaminolysis, and upregulated the citric acid cycle. The use of a glutaminase 1 inhibitor (CB-839) significantly curtailed senescence-associated stemness (SAS), underscoring the pivotal role of CD38 in driving glutaminolysis that contributes to d-flow-induced SAS. Moreover, the application of Ab68 but not IgG2a control decreased atherothrombosis formation following PLCL in LATS1/2-EKO mice. However, the effectiveness of Ab68 in attenuating atherosclerosis in wild-type mice was less pronounced. Conclusions: In the presence of d-flow, upregulated CD38, resulting from reduced LATS1/2 expression, triggers EC responses characterized by increased glutaminolysis and the emergence of an EC SAS phenotype. These processes play a crucial role in a unique form of atherothrombosis. Additionally, CD38’s impact on reducing PDH activity, along with YAP and CD38-mediated enhancement of glutaminolysis, constitutes critical pathways for inducing EC SAS by d-flow.

Background: Atherosclerotic plaques, especially high-risk ones, form in blood vessel regions exposed to d-flow. EC dysfunction induced by d-flow likely contributes to plaque development. In contrast, regions with laminar flow (l-flow) are less susceptible to plaque formation. Although the Hippo pathway is implicated in mechano-transduction, the exact role and molecular mechanisms of LATS1/2 in response to d-flow remain incompletely understood. Methods: We employed endothelial cell (EC)-specific Lats1 and Lats2 knockout mice within a partial left carotid ligation (PLCL) model to simulate disturbed flow conditions. We characterized plaques using imaging mass cytometry (IMC) and sequential immunofluorescence via COMET TM . Results: We investigated the effects of d-flow on YAP activity and LATS1/2 expression. While both l-flow and d-flow activate YAP activity, only d-flow leads to decreased LATS1/2 expression. We induced Lats1/2 deletion in tamoxifen-inducible Lats1 -/- /Lats2 -/- EKO mice. Within 14 days, all mice (27/27) died due to severe systemic edema and increased vascular permeability. In Lats1 +/- /Lats2 -/- EKO mice (LATS1/2-EKO), we observed atherothrombotic lesions characterized by increased EC proliferation and a senescence-associated secretory phenotype (SASP) in vivo . Mechanistically, d-flow reduces LATS1/2 expression, leading to increased CD38 expression. CD38 triggers not only SASP, but also senescence-associated stemness (SAS) via NAD + depletion, dependent on Lamin A but independent of YAP. We also explored the relationship between CD38 and Ki67 in plaques in vivo. We calculated the logarithm of the Ki67:CD38 expression ratio at the single-cell level using IMC/COMET data. Based on the trimodal density distribution of this parameter, we found that in one group, CD38 and Ki67 were linearly co-expressed, and the percentage of LATS1/2-depleted cells in this group exceeded that of wild type (WT) cells, suggesting that CD38’s pro-proliferative effects dominate under LATS1/2 depletion conditions, despite its role in inducing senescence. Lastly, inhibiting CD38 mitigated d EC SAS/SASP, and atherothrombosis under LATS1/2 depletion conditions. Conclusions: Reduced LATS1/2-mediated CD38 expression in response to d-flow leads to an EC response marked by increased SASP/SAS, ultimately contributing to atherothrombosis. While this phenomenon is common in human advanced coronary atherosclerosis, it is not observed in commonly used mouse models of atherosclerosis.

Background&Hypothesis: Nicotinamide adenine dinucleotide (NAD) is a critical coenzyme, essential for a variety of cellular processes. Pulmonary arterial hypertension (PAH) is associated with impaired metabolism and reduced NAD levels that contribute to its hyperproliferative state. CD38 is an ecto-enzyme that degrades NAD and produces several byproducts including cyclic ADPR. We hypothesized that CD38 mediates pathological reductions in NAD levels contributing to PAH vascular remodeling. Methods: To test this hypothesis, we evaluated expression levels of CD38 across PAH tissues, tested its functional role in human pulmonary artery endothelial cells (PAEC) and smooth muscle cells (PASMCs), and examined the response of a global CD38 knockout mouse ( CD38 -/- ) in an established chronic hypoxic (10% FiO2, 4 weeks) model of pulmonary hypertension. Results: CD38 expression was elevated in human PAECs derived from PAH cases and in rodent whole lung homogenates. Media from PAEC exposed to a CD38 inhibitor (78c) led to reduced PASMC proliferation. CD38 -/- mice exposed to chronic hypoxia exhibited attenuated PH compared to cage controls. Specifically, histological assessment of murine lungs revealed reduced PA medial thickness compared to control. CD38 -/- mice exhibited reduced right ventricular systolic pressure and a corresponding decrease in Fulton Index after hypoxic exposure. Consistent with these results, targeted metabolite measurements revealed that CD38 -/- mice exhibited elevated NAD levels in the lungs. Discussion: These results suggest that CD38 is a novel PAH target, and its deficiency restores NAD levels in the lungs and reduces pulmonary hypertension in mice.

Abstract Background Existing clinical preoperative risk assessment tools such as the Revised Cardiac Risk Index (RCRI) have been used extensively to predict perioperative major adverse cardiovascular events (MACE). Electrocardiogram (ECG) analysis using Deep Learning can identify hidden features that human eyes cannot identify and might help further risk stratify patients undergoing noncardiac surgery. Objective We aimed to develop a Deep Learning model that predicts perioperative MACE in patients undergoing elective noncardiac surgeries. Methods We included patients ≥ 18-year-old who underwent elective non-cardiac surgery between 2000-2021. MACE was validated in duplicate and were defined as a composite of in-hospital myocardial infarction, cardiac arrest or mortality. A convolutional neural network was developed using ECGs within 30 days before surgery. We randomly split subjects into training, internal validation, and testing datasets in a 7:1:2 ratio. Performance was evaluated using the area under the receiver operator characteristics curve (AUC) values on the testing dataset. Models trained included AI-ECG models to predict in-hospital MACE and to predict in-hospital mortality, and AI-ECG+RCRI models to predict in-hospital MACE and to predict in-hospital mortality. All models were validated using 30-day validated outcomes (MACE or all-cause mortality) in a community-based cohort and were compared with the Revised Cardiac Risk Index (RCRI) score using AUC values. Findings: We included 195,214 patients who underwent a total of 241,999 surgeries. 169,214 ECGs were used in the training dataset, 24,234 in the internal validation dataset, and 48,551 in the testing dataset. In the test cohort, the AI-ECG algorithm discriminated risk for in-hospital MACE with an AUC of 0.82 (95% CI 0.79-0.85). The algorithm similarly discriminated 30-day MACE with an AUC value of 0.79 (95% CI 0.77-0.81) surpassing the discrimination of the RCRI score AUC of 0.69 (95% CI 0.66-0.72). All models’ performances are shown in Figure1A. The AI-ECG model to predict in-hospital mortality had an AUC of 0.83 (95% CI 0.80-0.86) and predicted 30-day mortality with an AUC of 0.80 (95% CI 0.77-0.82). Other models’ performances are shown Figure1B. Training the AI-ECG models including RCRI data did not improve the AI-ECG models’ performance. Conclusion AI-ECG models with no additional clinical data can improve perioperative risk prediction in non-cardiac surgery, outperforming a conventional and widely used risk stratification tool such as the RCRI.

Abstract Aims Doxorubicin (DXR) is a chemotherapeutic agent that causes dose-dependent cardiotoxicity. Recently, it has been proposed that the NADase CD38 may play a role in doxorubicin-induced cardiotoxicity (DIC). CD38 is the main NAD+-catabolizing enzyme in mammalian tissues. Interestingly, in the heart, CD38 is mostly expressed as an ecto-enzyme that can be targeted by specific inhibitory antibodies. The goal of the present study is to characterize the role of CD38 ecto-enzymatic activity in cardiac metabolism and the development of DIC. Methods and results Using both a transgenic animal model and a non-cytotoxic enzymatic anti-CD38 antibody, we investigated the role of CD38 and its ecto-NADase activity in DIC in pre-clinical models. First, we observed that DIC was prevented in the CD38 catalytically inactive (CD38-CI) transgenic mice. Both left ventricular systolic function and exercise capacity were decreased in wild-type but not in CD38-CI mice treated with DXR. Second, blocking CD38-NADase activity with the specific antibody 68 (Ab68) likewise protected mice against DIC and decreased DXR-related mortality by 50%. A reduction of DXR-induced mitochondrial dysfunction, energy deficiency, and inflammation gene expression were identified as the main mechanisms mediating the protective effects. Conclusion NAD+-preserving strategies by inactivation of CD38 via a genetic or a pharmacological-based approach improve cardiac energetics and reduce cardiac inflammation and dysfunction otherwise seen in an acute DXR cardiotoxicity model.

Atherosclerotic and high-risk plaques are predominantly localized to vessel wall regions with non-laminar disturbed blood flow (d-flow), leading to the principle that d-flow-, but not laminar flow (l-flow)-driven endothelial cells (EC) dysfunction plays a role in this process. LATS1/2 and YAP are components of the Hippo signaling pathway that are involved in cellular responses to l-flow. The l-flow-mediated inhibition of LATS1/2 activity triggers YAP activation and maintains vascular structure. However, the role of Hippo signaling under d-flow remains unclear. Although both l- and d-flow increased YAP activity, only d-flow decreased LATS1/2 expression. Since the effects of l- and d-flow on EC differ, we studied the role of EC LATS1/2 using EC-specific Lats1 and 2 knock-out (EKO) mice. Within 14 days after inducing Lats1/2 deletion in tamoxifen-inducible Lats1 homo / Lats2 homo EKO mice, all the mice (27/27) died of severe systemic edema, accompanied by increased EC apoptosis and vascular permeability. We generated Lats1 he t / Lats2 homo -EKO mice ( Lats1 het /2 homo -EKO) and induced hypercholesteremia with AAV8-PCSK9 injections and a high-fat diet (HFD). After HFD, we detected plaque erosion-like plaque lesions at the d-flow areas, which revealed strongly fibrin/fibrinogen-positive organized thrombus (OTh) formation without sizeable necrotic cores. In Lats1 het /2 homo -EKO, we found significant increases in 1) EC proliferation, 2) EC apoptosis with senescent phenotype, 3) tissue factor (TF) expression, and 4) inflammation. Therefore, the phenotype observed in Lats1 het /2 homo -EKO represents a unique senescence-associated stemness (SAS) phenotype, which allows EC to escape senescence-induced cell cycle arrest. The EC proliferation induced by depletion of LATS1/2 was YAP-dependent. In contrast, EC senescence induced by CD38-mediated NAD + depletion was YAP-independent. These findings indicate that downregulating LATS1/2 expression-induced SAS leads to OTh via both YAP-dependent and independent mechanisms. OTh plays a key role in human atherosclerosis but is rarely observed in the mouse atherosclerosis model. Lats1 het /2 homo -EKO can provide a valuable platform for studying the mechanism and unique role of EC SAS-induced OTh formation.

AbstractBackgroundCD38 has been established as an important therapeutic target for multiple myeloma (MM), for which two CD38 antibodies are currently approved—daratumumab and isatuximab. CD38 is an ectoenzyme that degrades NAD and its precursors and is involved in the production of adenosine and other metabolites.AimAmong the various mechanisms by which CD38 antibodies can induce MM cell death is immunomodulation, including multiple pathways for CD38‐mediated T‐cell activation. Patients who respond to anti‐CD38 targeting treatment experience more marked changes in T‐cell expansion, activity, and clonality than nonresponders.ImplicationsResistance mechanisms that undermine the immunomodulatory effects of CD38‐targeting therapies can be tumor intrinsic, such as the downregulation of CD38 surface expression and expression of complement inhibitor proteins, and immune microenvironment‐related, such as changes to the natural killer (NK) cell numbers and function in the bone marrow niche. There are numerous strategies to overcome this resistance, which include identifying and targeting other therapeutic targets involved in, for example, adenosine production, the activation of NK cells or monocytes through immunomodulatory drugs and their combination with elotuzumab, or with bispecific T‐cell engagers.