BACKGROUND: Increasing evidence from preclinical models has linked the actions of brown adipose tissue (BAT) with protection against atherosclerosis and cardiovascular disease, in part due to its salutary effects on syst...BACKGROUND: Increasing evidence from preclinical models has linked the actions of brown adipose tissue (BAT) with protection against atherosclerosis and cardiovascular disease, in part due to its salutary effects on systemic lipid composition. However, human data on the role of BAT in atherosclerosis are scarce. METHODS: In this cross-sectional study, we examined 65 individuals with obesity and analyzed cold-induced BAT activity and vascular inflammation in the aorta using F-fluorodeoxyglucose positron emission tomography combined with computed tomography in combination with systemic lipidomics and proteomics analyses. RESULTS: We identified 21 subjects with cold-induced BAT (BAT positive), whereas 44 individuals had no significant BAT activity (BAT negative) after cold exposure. Both groups had similar age, sex distribution, body mass index, and classical cardiovascular risk profile. However, BAT-positive individuals had significantly less arterial inflammation as evidenced by lower F-fluorodeoxyglucose uptake in the ascending aorta and the aortic arch. Notably, BAT volume, SUV (mean standardized uptake value), and cold-induced thermogenesis correlated negatively with aortic inflammation, suggesting an atheroprotective role of BAT. Using unbiased lipidomics and proteomics analyses in plasma, we found that anti-inflammatory and potentially antiatherogenic circulating factors, such as cytochrome P450 oxylipin products and the serpin family member SERPINB12 (serpin family B member 12), were increased in BAT positive, whereas proatherogenic and prothrombotic factors, including acute phase protein ORM2 (orosomucoid 2), APOD (apolipoprotein D), FGA (fibrinogen A), and FGB (fibrinogen B), were significantly lower in individuals with active BAT. Likewise, the circulating concentrations of inflammatory markers, such as IL-6 (interleukin-6), were reduced in BAT positive versus BAT negative. CONCLUSIONS: Together, these data link human BAT function with protection against arterial inflammation and a potentially antiatherogenic and anti-inflammatory circulating profile. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02381483 and NCT03168009.
Ito W, Nakamichi R, Hishikawa A
… +13 more, Yoshimoto N, Nishimura ES, Hama EY, Maruki T, Iwabuchi S, Yoshida R, Toda M, Kosugi S, Yamaguchi S, Kanda T, Hashiguchi A, Itoh H, Hayashi K
BACKGROUND: Cardiovascular diseases increase with aging and are closely linked to metabolic dysfunction and kidney disease through the cardiovascular-kidney-metabolic axis, but the underlying molecular mechanisms remain...BACKGROUND: Cardiovascular diseases increase with aging and are closely linked to metabolic dysfunction and kidney disease through the cardiovascular-kidney-metabolic axis, but the underlying molecular mechanisms remain unclear. Accumulating evidence suggests that vascular endothelial cells (ECs) are particularly vulnerable to aging stressors, such as DNA damage. We investigated whether EC DNA damage drives cardiovascular-kidney-metabolic dysfunction. METHODS: We generated mice with EC-specific DNA double-strand breaks using an endonuclease I-PpoI and subjected them to a high-fat diet (HFD). This approach allowed us to investigate the impact of EC-specific DNA damage on cardiovascular, metabolic, and renal systems. Furthermore, we analyzed the correlation between EC DNA damage markers (γH2AX [phosphorylated histone H2AX]) and clinical parameters in human kidney biopsy samples. RESULTS: High-fat diet-fed endonuclease I-PpoI mice rapidly developed hypertension, dyslipidemia (low high-density lipoprotein cholesterol), hepatic steatosis, and visceral fat accumulation. Mechanistically, high-fat diet feeding compromised DNA repair capacity by suppressing ATM (ataxia-telangiectasia mutated) expression in the aorta. Consequently, DNA damage in aortic ECs triggered ET-1 (endothelin-1) secretion. This induced hepatic hypoxia and ETAR (endothelin type A receptor) activation, which promoted lipid metabolic reprogramming via ACSS2 (acetyl-CoA synthetase 2) upregulation. In addition, renal aging was accelerated. The selective ETAR antagonist atrasentan normalized blood pressure, reversed hepatic steatosis, restored high-density lipoprotein cholesterol, reduced visceral fat, and attenuated renal aging. In humans, EC DNA damage correlated negatively with estimated glomerular filtration rate and high-density lipoprotein cholesterol and positively with hepatic steatosis indices and renal cortical ETAR expression. CONCLUSIONS: Endothelial DNA damage is a pivotal driver of cardiovascular-kidney-metabolic dysfunction through the ET-1-ETAR-ACSS2 signaling cascade. ETAR blockade offers a mechanism-based therapeutic strategy for age-related cardiovascular, renal, and metabolic diseases.
Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disorder in which right heart failure remains the leading cause of morbidity and mortality. Although PAH occurs more frequently in women, female pati...Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disorder in which right heart failure remains the leading cause of morbidity and mortality. Although PAH occurs more frequently in women, female patients consistently demonstrate superior right ventricular (RV) function, more favorable RV-pulmonary arterial coupling, and improved survival compared with men-a phenomenon commonly referred to as the sex paradox in PAH. These observations highlight the central role of biological sex in shaping RV adaptation to chronic pressure overload and underscore RV dysfunction as an independent determinant of clinical outcomes in PAH. In this brief review, we synthesize emerging clinical, translational, and experimental evidence delineating sex-specific differences in RV adaptation and maladaptation in PAH. We focus on key biological processes that exhibit pronounced sexual dimorphism, including immune and inflammatory signaling, angiogenesis and microvascular remodeling, metabolic reprogramming and mitochondrial function, and fibrotic remodeling of the pressure-overloaded RV. Accumulating data indicate that estrogen signaling confers RV protection through coordinated effects on myocardial contractility, metabolic efficiency, angiogenic capacity, and immune regulation, whereas androgens and male-predominant pathways are associated with maladaptive hypertrophy, fibrosis, and earlier RV-pulmonary artery uncoupling. Importantly, these sex-linked mechanisms help explain why reductions in pulmonary vascular resistance alone are often insufficient to prevent right heart failure and why current PAH therapies exert limited direct effects on the RV. We further discuss the clinical implications of sex differences in PAH, including their relevance for risk stratification, therapeutic response, and trial design, and highlight emerging RV-directed therapeutic strategies targeting sex hormone signaling, immune pathways, metabolism, angiogenesis, and fibrosis. We discuss how hormonal states across the lifespan (eg, pregnancy, menopause, exogenous hormone exposure, and gender-affirming care) shape clinical outcomes in PAH. Finally, we identify key knowledge gaps and future directions needed to advance sex-informed, RV-centric precision medicine approaches for PAH.
BACKGROUND: The bidirectional interaction between inflammation and thrombus formation plays an important role in myocardial infarction (MI) with IL (interleukin)-6 as a central mediator. If anti-inflammatory therapy modu...BACKGROUND: The bidirectional interaction between inflammation and thrombus formation plays an important role in myocardial infarction (MI) with IL (interleukin)-6 as a central mediator. If anti-inflammatory therapy modulates coagulation factors, and platelet activation in patients with MI is not clear. METHODS: We have shown that tocilizumab, a monoclonal antibody targeting IL-6R (IL-6 receptor), improves myocardial salvage index in patients with ST-elevation MI. Herein, we measured levels of soluble markers of platelet activation (P-selectin, sCD40L [soluble CD40 ligand]) and coagulation (TF [tissue factor], TFPI [TF pathway inhibitor], PAI [plasminogen activator inhibitor]-1, and D-dimer) in 136 patients with ST-segment-elevation MI (70 tocilizumab and 66 placebo). Platelet-poor EDTA plasma samples were obtained at admission and after 24 and 168 hours. Temporal changes were related to TnT (troponin T), as well as infarct size and myocardial salvage index, assessed by cardiac magnetic resonance imaging. RESULTS: Our major findings were given as follows: (1) patients had higher sCD40L, P-selectin, TFPI, and D-dimer than 28 healthy controls, and these increased during 1-week follow-up, while TFPI decreased; (2) tocilizumab attenuated P-selectin in patients with short symptom duration at 24 hours in particular in those with high C-reactive protein, and this change correlated positively with indices of myocardial damage; (3) tocilizumab augmented TF at 168 hours, and this change correlated positively with infarct size and negatively with myocardial salvage index; (4) change in D-dimer at 168 hours correlated positively with infarct size and negatively with myocardial salvage index in particular in those with long symptom durations or treated with placebo; tocilizumab attenuated these changes; and (5) the use of heparin attenuated sCD40L levels and increased TFPI levels in admission samples and TF levels after 168 hours. CONCLUSIONS: Our findings support attenuation of platelet activation/coagulation by tocilizumab in patients with ST-segment-elevation MI. The marked rise in TF could be a hereto unrecognized side effects of tocilizumab, which need further investigation.
Lee-Kim VS, Schnitzler GR, Fang S
… +12 more, Mardani-Kamali N, Cai XS, Cui R, Barry AE, Zandavi M, Yoo HJ, Kant S, Mahajan R, Rao SSP, Aiden EL, Engreitz JM, Gupta RM
Arterioscler Thromb Vasc Biol
· 2026 Jun · PMID 42021732
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BACKGROUND: Coronary artery disease (CAD) is a complex condition and remains the leading cause of mortality worldwide. Genome-wide association studies have identified a CAD risk locus on chromosome 10q23 that is independ...BACKGROUND: Coronary artery disease (CAD) is a complex condition and remains the leading cause of mortality worldwide. Genome-wide association studies have identified a CAD risk locus on chromosome 10q23 that is independent of traditional risk factors, providing an opportunity to uncover novel molecular mechanisms contributing to CAD pathogenesis. METHODS: Improved fine-mapping approaches were used to prioritize noncoding variants at the 10q23 locus within the intronic region of (tetraspanin 14). Regulatory elements harboring lead variants were functionally interrogated using chromatin accessibility, 3-dimensional chromatin organization, and clustered regularly interspaced short palindromic repeats-mediated deletion approaches in endothelial cells (ECs). Subsequently, TSPAN14 function in ECs was assessed using transcriptomic profiling, Notch signaling activation assays, and EC functional assay using gene knockout (KO) cell lines. RESULTS: Fine-mapping identified 2 lead variants, rs17680741 and rs12260962, located within regulatory elements predicted to affect expression in monocytes and ECs, respectively. Chromatin accessibility, organization, and enhancer deletion assays demonstrated EC-specific function for the rs12260962-harboring regulatory element in expression regulation. Loss of resulted in significant transcriptomic changes related to Notch signaling, heart morphogenesis, cell adhesion, and wound healing. Functionally, ECs exhibited impaired cell-cell junction integrity, reduced repair capacity, and diminished mechanosensitive responses. CONCLUSIONS: Together, these data identify a regulatory element harboring CAD-associated variant at the 10q23 locus that modulates expression and downstream Notch signaling in ECs, thereby linking genetic risk to endothelial dysfunction relevant to CAD pathogenesis.
Qian F, Gajjar P, Prescott B
… +4 more, Mitchell GF, Xanthakis V, Rade JJ, Nayor M
Arterioscler Thromb Vasc Biol
· 2026 Jun · PMID 42021731
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BACKGROUND: Systemic thromboxane A generation, assessed via measurement of its urinary metabolites, is associated with cardiovascular disease (CVD) risk. Modifiable correlates with thromboxane A generation, including pot...BACKGROUND: Systemic thromboxane A generation, assessed via measurement of its urinary metabolites, is associated with cardiovascular disease (CVD) risk. Modifiable correlates with thromboxane A generation, including potential nonplatelet sources not readily affected by aspirin, are poorly understood. METHODS: We investigated 2655 FHS (Framingham Heart Study) participants with measurements of urinary thromboxane B metabolites normalized for renal function (TXB-M). Life's Essential 8 (LE8) score was constructed from 8 modifiable factors. We additionally examined erythrocyte omega-3 fatty acids and omega-6 fatty acid levels, namely, eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid. In a subset of participants, objective measurements of vascular stiffness and adiposity were obtained. We related these factors to TXB-M using linear models, adjusting for age, sex, and aspirin use. We also explored the association of LE8 or omega-3 fatty acids with total CVD or heart failure stratified by TXB-M. RESULTS: Both total LE8 score (<0.001) and individual LE8 components (<0.05 for each), including favorable diet, physical activity, blood glucose, blood pressure, and nonsmoking, were associated with lower TXB-M. Higher omega-3 fatty acids (eicosapentaenoic acid+docosahexaenoic acid) and lower arachidonic acid were associated with lower TXB-M (<0.005 for each). Higher TXB-M was related to greater waist circumference, computed tomography-measured visceral adipose tissue, and hepatic steatosis (<0.01 for each), and higher large artery vascular stiffness (<0.001). Findings were generally consistent across aspirin use status. After median follow-up of 12.9 years (371 CVD and 214 heart failure events), individuals with both high TXB-M and low LE8 displayed an over 5-fold higher risk of heart failure (hazard ratio, 5.07 [95% CI, 3.26-7.89]) and 2.5-fold higher risk of CVD (hazard ratio, 2.74 [95% CI, 2.04-3.68]) compared with participants with low TXB-M and high LE8. CONCLUSIONS: Our findings suggest several modifiable factors that may impact systemic thromboxane A generation. Higher systemic thromboxane A generation also appears to modulate the association of lifestyle measures (as assessed by LE8 score) with CVD and heart failure.
BACKGROUND: Endothelial-to-mesenchymal transition (EndMTE) is implicated in atherosclerosis by contributing to endothelial dysfunction (ED). SMS2 (sphingomyelin synthase 2), a key enzyme in sphingomyelin synthesis, plays...BACKGROUND: Endothelial-to-mesenchymal transition (EndMTE) is implicated in atherosclerosis by contributing to endothelial dysfunction (ED). SMS2 (sphingomyelin synthase 2), a key enzyme in sphingomyelin synthesis, plays a significant role in both ED and atherosclerosis. Nonetheless, the precise mechanisms of SMS2-associated ED, and its potential modulation via EndMT remain unexplored in the context of ED and atherosclerosis progression. METHODS: To investigate this, we inhibited SMS2 activity using the inhibitor Ly93 and performed RNA sequencing on human umbilical vein endothelial cells. Furthermore, we validated the potential mechanisms of EndMT in human umbilical vein endothelial cells, Apo E mice, and human atherosclerotic plaques. RESULTS: SMS2 inhibition suppressed EndMT by blocking the Wnt/β-catenin pathway. This blockade attenuated PPARγ (peroxisome proliferator-activated receptor gamma) ubiquitination-mediated degradation via PPARγ-β-catenin interaction, ultimately reducing CPT1A expression and fatty acid oxidation. In vivo, endothelial cell-specific overexpression of SMS2 in ApoE mice enhances atherosclerosis, and SMS2 positively correlates with Wnt/β-catenin, EndMT, and ED, but inversely correlates with PPARγ activity and fatty acid oxidation. Furthermore, in the unstable atherosclerosis plaques of humans, the expression of SMS2 in endothelial cells is significantly higher compared with that in stable plaques. The relationship between SMS2 and Wnt/β-catenin, EndMT, ED, PPARγ, and fatty acid oxidation aligns with the aforementioned findings. CONCLUSIONS: SMS2 can activate the Wnt/β-catenin pathway, which is inversely correlated with the activity of PPARγ and fatty acid oxidation. This process facilitates EndMT and ED, ultimately contributing to the initiation and development of atherosclerosis. These findings suggest that inhibition of endothelial SMS2 activity with Ly93 could be beneficial for the treatment of atherosclerosis.
Potassium ion channels are critical regulators of vascular homeostasis and cardiac electrophysiology that act by regulating the resting membrane potential via hyperpolarization or depolarization. They are modulated in re...Potassium ion channels are critical regulators of vascular homeostasis and cardiac electrophysiology that act by regulating the resting membrane potential via hyperpolarization or depolarization. They are modulated in response to intracellular or extracellular voltage or ion concentrations, which is key in preserving vascular tone and cardiac contractility. In vascular smooth muscle cells, large-conductance calcium-activated potassium channels are influenced by both intracellular calcium ion concentrations and during depolarization, whereas small- and intermediate-conductance channels are strictly dependent on intracellular calcium ions only, which in turn are regulated by ryanodine receptors of the sarcoplasmic reticulum. On the other hand, voltage-dependent potassium channels are activated by membrane depolarization, and the resting membrane potential is restored via negative feedback. Genome-wide association studies in humans identified variation in genes encoding voltage-dependent and 2-pore domain potassium ion channels as being associated with the risk of developing hypertension. In rodent models of hypertension, arterial expression and activity of large-conductance calcium-activated potassium channels are upregulated, whereas voltage-dependent, ATP-sensitive, and inward-rectifier potassium channels are downregulated. In cardiomyocytes, potassium currents play a key role in regulating cardiac action potential and refractory periods, with their dysregulation contributing to arrhythmogenesis. Given the therapeutic significance of potassium ion channels in antiarrhythmic treatments, we have reviewed their potential to exhibit blood pressure-lowering effects using evidence from human and animal studies. More research is warranted to investigate the significance of existing drugs, including amiodarone and sotalol, in the treatment of hypertension.
Crossey E, Carty S, Garza I
… +7 more, Perez M, Shao F, Al Abdullatif S, Campbell JD, Mizgerd JP, Fine A, Jones MR
Arterioscler Thromb Vasc Biol
· 2026 Jun · PMID 41988715
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BACKGROUND: Lung lymphatic drainage of interstitial fluid is essential for preventing pulmonary edema, a condition characterized by the accumulation of extravascular fluid that impedes respiratory gas exchange and can be...BACKGROUND: Lung lymphatic drainage of interstitial fluid is essential for preventing pulmonary edema, a condition characterized by the accumulation of extravascular fluid that impedes respiratory gas exchange and can be fatal. Beyond fluid regulation, lung lymphatics also serve as conduits for immune cell trafficking, supporting both surveillance and mounting of host immune responses during lung infection. Despite their essential roles, the cellular and functional heterogeneity of lung lymphatic endothelial cells (LECs) remains poorly defined. METHODS: Leveraging single-nucleus sequencing technology, we investigated LEC heterogeneity in the homeostatic adult mouse lung. RESULTS: We identified Stab2 (stabilin-2), a class H scavenger receptor, as a unique marker of a distinct subset of LECs in lymphatic vessels adjacent to pulmonary veins and in alveolar regions. A separate, distinct subset of LECs is defined by expression of Pkhd1l1 (polycystic kidney and hepatic disease 1-like-1), a component of stereocilia, and these lymphatic vessels are localized to the bronchovascular bundle. CONCLUSIONS: Our findings suggest that lung LECs are not a uniform population but instead comprise molecularly distinct and spatially organized lymphatic vessels, possibly with specialized functions. These results lay the groundwork for further studies geared toward understanding the roles of cellular origin in lung LEC heterogeneity, whether lymphatics in other organs have analogous spatial organization, and whether these disparate cells and vessels have functional differences in fluid homeostasis and immune regulation during pulmonary disease pathogenesis.
BACKGROUND: Vascular calcification is frequent among patients with chronic kidney disease, in which vascular smooth muscle cells (VSMCs) play a key pathological role. Our previous research revealed that the E3 ubiquitin...BACKGROUND: Vascular calcification is frequent among patients with chronic kidney disease, in which vascular smooth muscle cells (VSMCs) play a key pathological role. Our previous research revealed that the E3 ubiquitin ligase RNF10 (ring finger protein 10) regulates VSMC hyperproliferation and apoptosis; however, the function of RNF10 in vascular calcification remains unknown. METHODS: Serum RNF10 levels were assessed in 2 independent cross-sectional chronic kidney disease patient cohorts with vascular calcification. RNF10 expression was assessed in calcified rat aortas and VSMCs. The effects of RNF10 on vascular calcification were evaluated in knock-in rats and RNF10 overexpressed VSMCs. To investigate the underlying mechanism, RNA-seq (RNA sequencing), ChIP-seq (chromatin immunoprecipitation sequencing), ChIP-qPCR (chromatin immunoprecipitation quantitative PCR), and luciferase reporter assays were performed. Gain- and loss-of-function experiments targeting Rbpjk (recombination signal binding protein for immunoglobulin kappa J region) were conducted in vivo and in vitro. RESULTS: Circulating RNF10 levels were significantly reduced in chronic kidney disease patients with vascular calcification, and RNF10 protein expression was reduced in calcified rat aortas and VSMCs. knock-in alleviated vascular calcification without obvious adverse effects on other major organs. In vitro, RNF10 overexpression attenuated calcification and reduced the expression of osteogenic markers. Notably, pharmacological inhibition of the ubiquitin-proteasome system did not impair RNF10's anticalcific activity. Nuclear RNF10 expression was increased in calcified VSMCs, supporting a noncanonical and transcriptional regulatory role. Integrated analyses identified that RNF10 negatively regulated expression during vascular calcification, rather than acting through the ubiquitin-proteasome system. Moreover, viral overexpression partially reversed the protective effects of RNF10 in vivo and in vitro and increased osteogenic marker expression, whereas siRNA-mediated knockdown reduced the marker expression. CONCLUSIONS: RNF10 depletion serves as the initiating factor that triggers -driven osteogenic differentiation during chronic kidney disease-associated vascular calcification. The protective role of RNF10 involves negative expression regulation rather than E3 ubiquitin ligase activity. This RNF10- regulatory axis provides a new perspective for developing prevention and treatment strategies for vascular calcification.
Galeano-Otero I, Dominguez-Liste B, Asprón C
… +10 more, Fernández-Chacón M, Escacena-Izquierdo L, Del Toro R, Rojas-Torres M, Durán-Ruiz MC, Siegfried G, Ordóñez-Fernández A, Khatib AM, Rosado JA, Smani T
BACKGROUND: Post-ischemic neovascularization is crucial for cardiac repair after myocardial infarction (MI). While Orai1-dependent store-operated calcium entry is known to support angiogenesis, its specific role after MI...BACKGROUND: Post-ischemic neovascularization is crucial for cardiac repair after myocardial infarction (MI). While Orai1-dependent store-operated calcium entry is known to support angiogenesis, its specific role after MI remains unclear. METHODS: We stimulated human umbilical vein endothelial cells (ECs) with serum from patients with ST-segment-elevation MI to analyze proangiogenic mechanisms and to mimic the post-infarct systemic environment. We performed integrative analysis, including transcriptomics, proteomics, post-MI mouse heart single-cell RNA sequencing, and immunostaining. RESULTS: ST-segment-elevation MI serum enhanced angiogenesis by upregulating VEGF (vascular endothelial growth factor), Notch, and Ca signaling pathways in EC. Notably, it increased Orai1 expression and store-operated calcium entry activity, required for EC migration and proliferation. Consistently, Orai1 inhibition with CM4620 significantly impaired subintestinal venous plexus development in zebrafish embryos. Single-cell RNA sequencing confirmed Orai1 upregulation, particularly in tip cells and proliferating EC clusters, which was confirmed in peri-infarct regions of mouse hearts and in tip-like cells in a 3-dimensional culture model. Proteomics analysis revealed that Orai1 silencing dysregulated VEGF and Notch1-related proangiogenic proteins. Furthermore, IL (interleukin)-17A mimicked ST-segment-elevation MI serum, inducing Orai1-mediated store-operated calcium entry and EC migration. CONCLUSIONS: Together, these findings reveal a novel role for the Orai1-dependent mechanism in post-MI angiogenesis, highlighting Orai1 as a potential therapeutic target for cardiac repair.
Fang Y, Zhang Z, Cao Q
… +20 more, Li Y, Duan Y, Meng P, Duan Z, Wang G, Gao J, Hua M, Huang B, Zhou T, Zhang H, Kong F, Zhang Y, Li M, Ma ZS, Li Y, Wang Z, Cheng R, Lu Q, Ni H, Lai R
BACKGROUND: ApoB (apolipoprotein B)-containing lipoproteins are causal risk factors for atherosclerotic coronary artery disease (CAD). Since LL-37 (human cathelicidin peptide) binds to ApoB-100 in this pathological conte...BACKGROUND: ApoB (apolipoprotein B)-containing lipoproteins are causal risk factors for atherosclerotic coronary artery disease (CAD). Since LL-37 (human cathelicidin peptide) binds to ApoB-100 in this pathological context, we investigated whether the circulating LL-37-ApoB-100 complex could serve as a biomarker for CAD. METHODS: We performed surface plasmon resonance and protein-protein docking to demonstrate the direct LL-37-ApoB-100 interaction. We developed a specific polyclonal antibody against the complex and measured its levels in human atherosclerotic plaques and plasma, as well as in mice. An observational case-control study of 1103 patients undergoing coronary angiography from 2 independent centers assessed the association between LL-37-ApoB-100 and obstructive CAD. RESULTS: We identified that LL-37 directly interacted with multiple distinct binding sites on ApoB-100. Plasma levels of LL-37-ApoB-100 complex were significantly elevated in human patients with atherosclerosis. Consistently, levels of this complex were positively correlated with atherosclerotic plaque area in mice. In the observational cohort from center 1, plasma LL-37-ApoB-100 levels were also significantly elevated in patients with obstructive CAD and strongly correlated with disease severity (Gensini score; =0.60, <0.001). Receiver operating characteristic curve analysis further demonstrated that LL-37-ApoB-100 was a valuable biomarker for the diagnosis of obstructive CAD, with an area under the curve of 0.82 (95% CIs, 0.81-0.85, <0.001). After adjustment for lipid and clinical measures, elevated LL-37-ApoB-100 levels remained an independent predictor of obstructive CAD, with an adjusted odds ratio of 6.51 (95% CI, 4.34-9.77, <0.001) for the upper quartiles. Observational analyses in center 2 showed consistent results. CONCLUSIONS: Circulating LL-37-ApoB-100 levels are strongly associated with angiographically documented CAD, highlighting LL-37-ApoB-100 as an independent predictor for CAD.
Nicholas SE, Helming SB, Ménoret A
… +11 more, Pathoulas CL, Xu MM, Hensel J, Kimble AL, Heineman B, Jellison ER, Reese B, Zhou B, Rodriguez-Oquendo A, Vella AT, Murphy PA
Arterioscler Thromb Vasc Biol
· 2026 Jun · PMID 41953979
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BACKGROUND: Atherosclerotic plaques form through lipid and immune cell accumulation beneath the arterial endothelium. CD8 (cluster of differentiation 8) T cells are abundant in lesions, and their activation correlates wi...BACKGROUND: Atherosclerotic plaques form through lipid and immune cell accumulation beneath the arterial endothelium. CD8 (cluster of differentiation 8) T cells are abundant in lesions, and their activation correlates with cardiovascular disease severity. Although endothelial cells recruit CD8 T cells to low and disturbed flow regions, whether they regulate CD8 activation and persistence is unknown. These interactions may be mediated by posttranscriptional control of mRNA translation. METHODS: We used ribosomal profiling in ); mice to assess posttranscriptional regulation in atherosclerotic endothelium in a partial carotid ligation model. We then used (endothelial cell-knockout) mice to examine the impact of endothelial Elavl1 (ELAV-like RNA-binding protein 1) on gene expression programs and immune cell activity. RESULTS: Elavl1 motifs were enriched near alternative splicing events, and within 5' untranslated regions of transcripts with altered ribosomal association in atherosclerosis. Elavl1 suppressed gene expression programs occurring in atherogenic endothelium, as deletion enhanced these responses and reduced CD8 T-cell accumulation (≈70%) at plaques without affecting recruitment, consistent with impaired persistence. In vitro, Elavl1-deficient endothelial cells suppressed antigen-dependent CD8 T-cell persistence, even in the presence of wild-type myeloid antigen-presenting cells and cognate antigen. CONCLUSIONS: Endothelial Elavl1 suppression enables endothelial cells to function as local immune checkpoint-like regulators of CD8 T-cell persistence in atherosclerosis. Thus, endothelial Elavl1 is a key regulator of adaptive immunity.
The placenta is a highly specialized organ that ensures the developing fetus gets adequate oxygen and nutrients from its mother. The placenta shares common development pathways with the fetal heart and releases factors t...The placenta is a highly specialized organ that ensures the developing fetus gets adequate oxygen and nutrients from its mother. The placenta shares common development pathways with the fetal heart and releases factors that can influence the way the mother's heart functions. Thus, pregnancy complications, where the placenta fails to develop properly, can lead to the development of fetal heart defects and induce long-term maternal cardiac dysfunction. In this review, we focus on how the placenta shapes cardiac events during development and the subsequent long-term impact on the offspring's heart. We also touch upon the potential role the placenta plays in maternal heart function.