BACKGROUND. Although traditional lipid parameters and coronary imaging techniques are valuable for cardiovascular disease (CVD) risk prediction, better diagnostic tests are still needed. METHODS. In a prospective, observational study, 795 subjects had extensive cardiometabolic profiling, including emerging biomarkers, such as apolipoprotein E (ApoE)-containing HDL-cholesterol. Coronary artery calcium (CAC) score was assessed in the entire cohort, and quantitative coronary computed tomography angiographic (CCTA) characterization (Medis, Qangio) of total (TB), non-calcified (NCB) and fibrous plaque burden (FB) was performed in a sub-cohort (n=300) of patients stratified by concentration of ApoE-HDL-C. Total and HDL-containing apolipoprotein C-III (ApoC-III) were also measured. RESULTS. Most patients had a clinical diagnosis of coronary artery disease (CAD) (n=80.4% of 795), with mean age of 59 years, male (57%) and about half on statin treatment. The low ApoE-HDL-C group had more severe stenosis (11% vs. 2%, overall P<0.001), with higher CAC as compared to high ApoE-HDL-C. On quantitative CCTA, high ApoE-HDL-C group had lower NCB (β=-0.24, P=0.0001), which tended to be significant in fully adjusted model (β=-0.32, P=0.001) and altered by ApoC-III in HDL levels. Low ApoE-HDL-C was significantly associated with LDL particle number (β=0.31; P=0.0001). Finally, when stratified by FB, ApoC-III in HDL showed a more robust predictive value of CAD over ApoE-HDL-C (AUC: 0.705, P=0.0001) in a fully adjusted model. CONCLUSIONS. ApoE-containing HDL-C showed a significant association with early coronary plaque characteristics and is affected by the presence of ApoC-III, indicating that low ApoE-HDL-C and high ApoC-III may be important markers of CVD severity. CLINICAL TRIAL REGISTRATION. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01621594. FUNDING. This work was supported by the National Heart, Lung and Blood Institute (NHLBI) at the National Institutes of Health Intramural Research Program. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Alexander V. Sorokin, Nidhi Patel, Khaled M. Abdelrahman, Clarence Ling, Mart Reimund, Giorgio Graziano, Maureen Sampson, Martin Playford, Amit K. Dey, Aarthi Reddy, Heather L. Teague, Michael Stagliano, Marcelo Amar, Marcus Y. Chen, Nehal Mehta, Alan T. Remaley
Hereditary hemorrhagic telangiectasia (HHT) patients have arteriovenous malformations (AVMs) with genetic mutations involving the activin-A receptor like type 1 (ACVRL1 or ALK1) and endoglin (ENG). Recent study showed that Neuropilin-1 (NRP-1) inhibits ALK1. We investigated the expression of NRP-1 in livers of patients with HHT and found that there was a significant reduction in NRP-1 in perivascular smooth muscle cells (SMCs). We used Nrp1SM22KO mice (Nrp1 was ablated in SMCs) and found hemorrhage, increased immune cell infiltration with decrease in SMCs and pericyte lining in lungs and liver in adult mice. Histologic examination revealed lung AVFs with enlarged liver vessels. Evaluation of the retina vessels at post-natal day 5 from Nrp1SM22KO mice demonstrated dilated capillaries with a reduction of pericytes. In inflow artery of surgical AVFs from the Nrp1SM22KO vs. WT mice, there was a significant decrease in Tgfb1, Eng and Alk1 expression, phosphorylated-SMAD (pSMAD)1/5/8, with an increase in apoptosis. TGF-β1 stimulated aortic SMCs from Nrp1SM22KO vs. WT mice have decreased pSMAD1/5/8 upon and increased apoptosis. Coimmunoprecipitation experiments revealed that NRP-1 interacts with ALK1 and ENG in SMCs. In sum, NRP-1 deletion in SMCs leads to reduced ALK1, ENG, pSMAD1/5/8 signaling, and cell death associated with AVM formation.
Sreenivasulu Kilari, Ying Wang, Avishek Singh, Rondell P. Graham, Vivek Iyer, Scott M. Thompson, Michael S. Torbenson, Debabrata Mukhopadhyay, Sanjay Misra
Severe COVID-19 disease is associated with dysregulation of the myeloid compartment during acute infection. Survivors frequently experience long-lasting sequelae but little is known about the eventual persistence of this immune alteration. Herein, we evaluated Toll-like receptor-induced cytokine responses in a cohort of mild to critical patients during acute or convalescent phases (n=97). In the acute phase, we observed impaired cytokine production by monocytes in the most severe patients. This capacity was globally restored in convalescent patients. Yet, we observed increased responsiveness to TLR1/2 ligation in patients that recovered from severe disease, indicating that these cells display distinct functional properties at the different stages of the disease. We identified a specific transcriptomic and epigenomic state in monocytes from acute severe patients that can account for their functional refractoriness. The molecular profile of monocytes from recovering patients was distinct and characterized by increased chromatin accessibility at AP1 and MAF loci. These results demonstrate that severe COVID-19 infection has a profound impact on the differentiation status and function of circulating monocytes both during the acute and the convalescent phases in a completely distinct manner. This could have important implications for our understanding of short and long-term COVID19-related morbidity.
Elisa Brauns, Abdulkader Azouz, David Grimaldi, Hanxi Xiao, Séverine Thomas, Muriel Nguyen, Véronique Olislagers, Ines Vu Duc, Carmen Orte Cano, Véronique Del Marmol, Pieter Pannus, Frédérick Libert, Sven Saussez, Nicolas Dauby, Jishnu Das, Arnaud Marchant, Stanislas Goriely
Atrial natriuretic peptide (ANP), encoded by Nppa, is a vasodilatory hormone that promotes salt excretion. Genome-wide association studies identified Nppa as a causative factor of blood pressure development, and in humans, ANP levels were suggested as an indicator of salt sensitivity. This study aimed to provide insights into the effects of ANP on cardiorenal function in salt-sensitive hypertension. To address this question, hypertension was induced in SSNPPA-/- (knockout of Nppa in the Dahl Salt-Sensitive (SS) rat background) or SSWT (wild type Dahl SS) rats by a high salt diet challenge (HS, 4% NaCl for 21 days). Chronic infusion of ANP in SSWT rats attenuated the increase in blood pressure and cardiorenal damage. Overall, SSNPPA-/- strain demonstrated higher blood pressure and intensified cardiac fibrosis (with no changes in ejection fraction) compared to SSWT rats. Furthermore, SSNPPA-/- rats exhibited kidney hypertrophy and higher glomerular injury scores, reduced diuresis, and lower sodium and chloride excretion than SSWT when fed a HS diet. Additionally, the activity of epithelial Na+ channel (ENaC) was found to be increased in the collecting ducts of the SSNPPA-/- rats. Taken together, these data show promise for the therapeutic benefits of ANP and ANP-increasing drugs for treating salt-sensitive hypertension.
Daria V. Ilatovskaya, Vladislav Levchenko, Kristen Winsor, Gregory R. Blass, Denisha R. Spires, Elizaveta Sarsenova, Iuliia Polina, Adrian Zietara, Mark Paterson, Alison J. Kriegel, Alexander Staruschenko
To elicit effective anti-tumor responses, CD8+ T cells need to infiltrate tumors and sustain their effector function within the immunosuppressive tumor microenvironment. Here we evaluate the role of MNK kinase activity in regulating CD8+ T cell infiltration and anti-tumor activity in pancreatic and thyroid tumors. We first show that human pancreatic and thyroid tumors with increased MNK kinase activity are associated with decreased infiltration by CD8+ T cells. We then show that while MNK inhibitors increase CD8+ T cells in these tumors, they induce a T cell exhaustion phenotype in the tumor microenvironment. Mechanistically, we show that the exhaustion phenotype is not caused by upregulation of PD-L1 but by tumor-associated macrophages (TAMs) becoming more immunosuppressive following MNK inhibitor treatment. Reversal of CD8+ T cell exhaustion by an anti-PD-1 antibody or TAM depletion synergizes with MNK inhibitors to control tumor growth and prolong animal survival. Importantly, we show in ex vivo human pancreatic tumor slice cultures that MNK inhibitors increase the expression of markers associated with immunosuppressive TAMs. Together, these findings demonstrate a previously unknown role of MNK kinases in modulating a pro-tumoral phenotype in macrophages and identify combination regimens involving MNK inhibitors to enhance anti-tumor immune responses.
Thao N.D. Pham, Christina Spaulding, Mario A. Shields, Anastasia E. Metropulos, Dhavan N. Shah, Mahmoud G. Khalafalla, Daniel R. Principe, David J. Bentrem, Hidayatullah G. Munshi
Wound repair following acute injury requires a coordinated inflammatory response. Type I interferon (IFN) signaling is important for regulating the inflammatory response post- skin injury. IFN kappa (IFNκ), a type I IFN, has recently been found to drive skin inflammation in lupus and psoriasis; however, the role of IFNκ in the context of normal or dysregulated wound healing is unclear. Here, we found that Infκ expression is upregulated in keratinocytes early post-injury and is essential for normal tissue repair. Under diabetic conditions, IFNκ was decreased in wound keratinocytes, and early inflammation was impaired. Further, we found that the histone methyltransferase MLL1 is upregulated early following injury and regulates Infκ expression in diabetic wound keratinocytes via an H3K4me3 mediated mechanism. Using a series of in vivo studies with a genetically engineered mouse model (Mll1fl/fl K14cre-) and human wound tissues from patients with T2D, we demonstrate that MLL1 controls wound keratinocyte-mediated Infκ and MLL1 is decreased in T2D keratinocytes. Importantly, we find the administration of IFNκ early following injury improves diabetic tissue repair through increasing early inflammation, collagen deposition, and re-epithelialization. These findings have significant implications for understanding the complex role type I interferons play in keratinocytes in normal and diabetic wound healing. Additionally, they suggest IFNκ may be a viable therapeutic target to improve diabetic wound repair.
Sonya J. Wolf, Christopher O. Audu, Amrita Joshi, Aaron D. denDekker, William J. Melvin, Frank M. Davis, Xianying Xing, Rachael Wasikowski, Lam Tsoi, Steven Kunkel, Johann E. Gudjonsson, Mary X. O'Riordan, J. Michelle Kahlenberg, Katherine A. Gallagher
Post-exertional malaise (PEM) is a hallmark symptom of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We monitored the evolution of 1,157 plasma metabolites in 60 ME/CFS cases (45 females, 15 males) and in 45 matched healthy control subjects (30 females, 15 males) before and after two maximal Cardiopulmonary Exercise Test (CPET) challenges separated by 24 hours, with the intent of provoking PEM in patients. Four timepoints allowed exploration of the metabolic response to maximal energy-producing capacity and the recovery pattern of ME/CFS cases compared to the healthy control group. Baseline comparison identified several significantly different metabolites, along with an enriched percentage of yet-to-be identified compounds. Additionally, temporal measures demonstrated an increased metabolic disparity between cohorts, including unknown metabolites. The effects of exertion in the ME/CFS cohort predominantly highlighted lipid- as well as energy-related pathways and chemical structure clusters, which were disparately affected by the first and second exercise sessions. The 24-hour recovery period was distinct in the ME/CFS cohort, with over a quarter of the identified pathways statistically different. The pathways that are uniquely different 24 hours after an exercise challenge provide clues to metabolic disruptions that lead to PEM. Numerous altered pathways were observed to depend on glutamate metabolism, a crucial component to the homeostasis of many organs in the body, including the brain.
Arnaud Germain, Ludovic Giloteaux, Geoffrey E. Moore, Susan M. Levine, John K. Chia, Betsy A. Keller, Jared Stevens, Carl J. Franconi, Xiangling Mao, Dikoma C. Shungu, Andrew Grimson, Maureen R. Hanson
Arterial stiffness predicts cardiovascular disease and all-cause mortality but its treatment remains challenging. Mice treated with angiotensin-II (Ang-II) develop hypertension, arterial stiffness, vascular dysfunction, and a downregulation of Rho-related BTB domain-containing protein 1 (RhoBTB1) in the vasculature. RhoBTB1 is associated with blood pressure regulation but its function is poorly understood. We tested the hypothesis that restoring RhoBTB1 can attenuate arterial stiffness, hypertension, and vascular dysfunction in Ang-II-treated mice. Genetic complementation of RhoBTB1 in the vasculature was achieved utilizing mice expressing a tamoxifen-inducible, smooth muscle-specific RhoBTB1 transgene. RhoBTB1 restoration efficiently and rapidly alleviated arterial stiffness, but not hypertension or vascular dysfunction. Mechanistic studies revealed that RhoBTB1 had no substantial effect on several classical arterial stiffness contributors such as collagen deposition, elastin content, and vascular smooth muscle remodeling. Instead, Ang-II increased actin polymerization in the aorta which was reversed by RhoBTB1. Changes in the levels of two regulators of actin polymerization, Cofilin and Vasodilator Stimulated Phosphoprotein (VASP), in response to RhoBTB1 were consistent with an actin depolymerization mechanism. Our study reveals an important function of RhoBTB1 and demonstrates its vital role in antagonizing established arterial stiffness and further supports a functional and mechanistic separation between hypertension, vascular dysfunction, and arterial stiffness.
Shi Fang, Jing Wu, John J. Reho, Ko-Ting Lu, Daniel T. Brozoski, Gaurav Kumar, Alec M. Werthman, Sebastiao Donato Silva Jr, Patricia C. Muskus Veitia, Kelsey K. Wackman, Angela J Mathison, Bi Qing Teng, Chien-Wei Lin, Frederick W. Quelle, Curt D. Sigmund
The lung airways are constantly exposed to inhaled toxic substances, resulting in cellular damage that is repaired by local expansion of resident bronchiolar epithelial club cells. Disturbed bronchiolar epithelial damage repair lays at the core of many prevalent lung diseases including chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, and lung cancer. However, it is still not known how bronchiolar club cell energy-metabolism contributes to this process. Here we show that Adipose TriGlyceride Lipase (ATGL), the rate-limiting enzyme for intracellular lipolysis, is critical for normal club cell function in mice. Deletion of the gene encoding ATGL, Pnpla2 (Atgl), induced substantial triglyceride accumulation, decreased mitochondrial numbers and decreased mitochondrial respiration in club cells. This defect manifested as bronchiolar epithelial thickening and increased airway resistance under baseline conditions. After naphthalene induced epithelial denudation, a regenerative defect was apparent. Mechanistically, dysfunctional PPARα lipid-signaling underlies this phenotype because, (i) ATGL was needed for PPARα lipid-signalling in regenerating bronchioles, and (ii) administration of the specific PPARα agonist WY14643 restored normal bronchiolar club cell ultrastructure and regenerative potential. Our data emphasize the importance of the cellular energy-metabolism for lung epithelial regeneration and highlight the significance of ATGL mediated lipid catabolism for lung health.
Manu Manjunath Kanti, Isabelle Striessnig-Bina, Beatrix I. Wieser, Silvia Schauer, Gerd Leitinger, Thomas O. Eichmann, Martina Schweiger, Margit Winkler, Elke Winter, Andrea Lana, Iris Kufferath, Leigh M. Marsh, Grazyna Kwapiszewska, Rudolf Zechner, Gerald Hoefler, Paul W. Vesely
Uveal melanoma (UM) represents a unique disease in that patients with primary UM are well stratified based on their risk of developing metastasis yet there are limited effective treatments once metastases occur. There is an urgent need to better understand the distinct molecular pathogenesis of UM and characteristics of patients at high risk for metastasis, to identify neo-antigenic targets which can be used in immunotherapy, and develop novel therapeutic strategies that may effectively target this lethal transition. An important and overlooked area of molecular pathogenesis and neoantigenic targets in UM come from human endogenous retroviruses (HERVs). We investigated the HERV expression landscape in primary UM and found that tumors stratified into four HERV-based subsets that provide clear delineation of risk outcome and support subtypes identified by other molecular indicators. Specific HERV loci are associated with the risk of uveal melanoma metastasis and may offer mechanistic insights into this process, including dysregulation of HERVs on chromosomes 3 and 8. A HERV signature comprised of 17 loci was sufficient to classify tumors according to subtype with >95% accuracy, including at least one intergenic HERV with coding potential (HERVE_Xp11.23) that could represent a new potential HERV E target for immunotherapy.
Matthew L. Bendall, Jasmine H. Francis, Alexander N. Shoushtari, Douglas F. Nixon
No posts were found with this tag.