Circulation research最新文献

{"title":"CD163⁺ Macrophages Induce Endothelial-to-Mesenchymal Transition in Atheroma.","authors":"Masayuki Mori, Atsushi Sakamoto, Rika Kawakami, Liang Guo, Lotte Slenders, Jose Verdezoto Mosquera, Saikat Kumar B Ghosh, Marian Wesseling, Tatsuya Shiraki, Arielle Bellissard, Palak Shah, Craig C Weinkauf, Takao Konishi, Yu Sato, Anne Cornelissen, Kenji Kawai, Hiroyuki Jinnouchi, Weili Xu, Aimee E Vozenilek, Desiree Williams, Takamasa Tanaka, Teruo Sekimoto, Michael C Kelly, Raquel Fernandez, Alyssa Grogan, A J Coslet, Alisa Fedotova, Anjali Kurse, Michal Mokry, Maria E Romero, Frank D Kolodgie, Gerard Pasterkamp, Clint L Miller, Renu Virmani, Aloke V Finn","doi":"10.1161/CIRCRESAHA.123.324082","DOIUrl":"10.1161/CIRCRESAHA.123.324082","url":null,"abstract":"<p><strong>Background: </strong>Cell phenotype switching is increasingly being recognized in atherosclerosis. However, our understanding of the exact stimuli for such cellular transformations and their significance for human atherosclerosis is still evolving. Intraplaque hemorrhage is thought to be a major contributor to plaque progression in part by stimulating the influx of CD163⁺ macrophages. Here, we explored the hypothesis that CD163⁺ macrophages cause plaque progression through the induction of proapoptotic endothelial-to-mesenchymal transition (EndMT) within the fibrous cap.</p><p><strong>Methods: </strong>Human coronary artery sections from CVPath's autopsy registry were selected for pathological analysis. Athero-prone <i>ApoE</i>^<i>-/-</i> and <i>ApoE</i>^<i>-/-</i><i>/CD163</i>^<i>-/-</i> mice were used for in vivo studies. Human peripheral blood mononuclear cell-induced macrophages and human aortic endothelial cells were used for in vitro experiments.</p><p><strong>Results: </strong>In 107 lesions with acute coronary plaque rupture, 55% had pathological evidence of intraplaque hemorrhage in nonculprit vessels/lesions. Thinner fibrous cap, greater CD163⁺ macrophage accumulation, and a larger number of CD31/FSP-1 (fibroblast specific protein-1) double-positive cells and TUNEL (terminal deoxynucleotidyl transferase-dUTP nick end labeling) positive cells in the fibrous cap were observed in nonculprit intraplaque hemorrhage lesions, as well as in culprit rupture sections versus nonculprit fibroatheroma sections. Human aortic endothelial cells cultured with supernatants from hemoglobin/haptoglobin-exposed macrophages showed that increased mesenchymal marker proteins (transgelin and FSP-1) while endothelial markers (VE-cadherin and CD31) were reduced, suggesting EndMT induction. Activation of NF-κB (nuclear factor kappa β) signaling by proinflammatory cytokines released from CD163⁺ macrophages directly regulated the expression of Snail, a critical transcription factor during EndMT induction. Western blot analysis for cleaved caspase-3 and microarray analysis of human aortic endothelial cells indicated that apoptosis was stimulated during CD163⁺ macrophage-induced EndMT. Additionally, <i>CD163</i> deletion in athero-prone mice suggested that CD163 is required for EndMT and plaque progression. Using single-cell RNA sequencing from human carotid endarterectomy lesions, a population of EndMT was detected, which demonstrated significant upregulation of apoptosis-related genes.</p><p><strong>Conclusions: </strong>CD163⁺ macrophages provoke EndMT, which may promote plaque progression through fibrous cap thinning.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e4-e23"},"PeriodicalIF":16.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141300156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Characteristics and Mechanisms of Acute Myocarditis.","authors":"Stephane Heymans, Sophie Van Linthout, Sarah Mignon Kraus, Leslie T Cooper, Ntobeko A B Ntusi","doi":"10.1161/CIRCRESAHA.124.324674","DOIUrl":"10.1161/CIRCRESAHA.124.324674","url":null,"abstract":"<p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT05335928.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 2","pages":"397-411"},"PeriodicalIF":16.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined Lipid Disturbances: More Than the Sum of Their Parts?","authors":"Robert A Hegele","doi":"10.1161/CIRCRESAHA.124.324793","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.324793","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 2","pages":"277-279"},"PeriodicalIF":16.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRIM35 Monoubiquitinates H2B in Cardiac Cells, Implications for Heart Failure.","authors":"Maria Areli Lorenzana-Carrillo, Saymon Tejay, Joseph Nanoa, Guocheng Huang, Yongsheng Liu, Alois Haromy, Yuan Yuan Zhao, Michelle Mendiola Pla, Dawn E Bowles, Adam Kinnaird, Evangelos D Michelakis, Gopinath Sutendra","doi":"10.1161/CIRCRESAHA.123.324202","DOIUrl":"10.1161/CIRCRESAHA.123.324202","url":null,"abstract":"<p><strong>Background: </strong>The tumor suppressor and proapoptotic transcription factor P53 is induced (and activated) in several forms of heart failure, including cardiotoxicity and dilated cardiomyopathy; however, the precise mechanism that coordinates its induction with accessibility to its transcriptional promoter sites remains unresolved, especially in the setting of mature terminally differentiated (nonreplicative) cardiomyocytes.</p><p><strong>Methods: </strong>Male and female control or TRIM35 (tripartite motif containing 35) overexpression adolescent (aged 1-3 months) and adult (aged 4-6 months) transgenic mice were used for all in vivo experiments. Primary adolescent or adult mouse cardiomyocytes were isolated from control or TRIM35 overexpression transgenic mice for all in vitro experiments. Adenovirus or small-interfering RNA was used for all molecular experiments to overexpress or knockdown, respectively, target genes in primary mouse cardiomyocytes. Patient dilated cardiomyopathy or nonfailing left ventricle samples were used for translational and mechanistic insight. Chromatin immunoprecipitation and DNA sequencing or quantitative real-time polymerase chain reaction (qPCR) was used to assess P53 binding to its transcriptional promoter targets, and RNA sequencing was used to identify disease-specific signaling pathways.</p><p><strong>Results: </strong>Here, we show that E3-ubiquitin ligase TRIM35 can directly monoubiquitinate lysine-120 (K120) on histone 2B in postnatal mature cardiomyocytes. This epigenetic modification was sufficient to promote chromatin remodeling, accessibility of P53 to its transcriptional promoter targets, and elongation of its transcribed mRNA. We found that increased P53 transcriptional activity (in cardiomyocyte-specific <i>Trim35</i> overexpression transgenic mice) was sufficient to initiate heart failure and these molecular findings were recapitulated in nonischemic human LV dilated cardiomyopathy samples.</p><p><strong>Conclusions: </strong>These findings suggest that TRIM35 and the ^K120Ub-histone 2B epigenetic modification are molecular features of cardiomyocytes that can collectively predict dilated cardiomyopathy pathogenesis.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"301-313"},"PeriodicalIF":16.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141300157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutrophil Cathepsin G and Thrombosis in COVID-19.","authors":"Francesco Violi, Simona Bartimoccia, Roberto Cangemi, Cristina Nocella, Alessandra D'Amico, Alessandra Oliva, Mario Venditti, Francesco Pugliese, Claudio Maria Mastroianni, Lorenzo Ridola, Miriam Lichtner, Vincenzo Cardinale, Domenico Alvaro, Vittoria Cammisotto, Valentina Castellani, Pasquale Pignatelli, Roberto Carnevale","doi":"10.1161/CIRCRESAHA.124.324649","DOIUrl":"10.1161/CIRCRESAHA.124.324649","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"350-352"},"PeriodicalIF":16.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tipifarnib Reduces Extracellular Vesicles and Protects From Heart Failure.","authors":"Vandana Mallaredy, Rajika Roy, Zhongjian Cheng, Charan Thej, Cindy Benedict, May Truongcao, Darukeshwara Joladarashi, Ajit Magadum, Jessica Ibetti, Maria Cimini, Carolina Gonzalez, Venkata Naga Srikanth Garikipati, Walter J Koch, Raj Kishore","doi":"10.1161/CIRCRESAHA.123.324110","DOIUrl":"10.1161/CIRCRESAHA.123.324110","url":null,"abstract":"<p><strong>Background: </strong>Heart failure (HF) is one of the leading causes of mortality worldwide. Extracellular vesicles, including small extracellular vesicles or exosomes, and their molecular cargo are known to modulate cell-to-cell communication during multiple cardiac diseases. However, the role of systemic extracellular vesicle biogenesis inhibition in HF models is not well documented and remains unclear.</p><p><strong>Methods: </strong>We investigated the role of circulating exosomes during cardiac dysfunction and remodeling in a mouse transverse aortic constriction (TAC) model of HF. Importantly, we investigate the efficacy of tipifarnib, a recently identified exosome biogenesis inhibitor that targets the critical proteins (Rab27a [Ras associated binding protein 27a], nSMase2 [neutral sphingomyelinase 2], and Alix [ALG-2-interacting protein X]) involved in exosome biogenesis for this mouse model of HF. In this study, 10-week-old male mice underwent TAC surgery were randomly assigned to groups with and without tipifarnib treatment (10 mg/kg 3 times/wk) and monitored for 8 weeks, and a comprehensive assessment was conducted through performed echocardiographic, histological, and biochemical studies.</p><p><strong>Results: </strong>TAC significantly elevated circulating plasma exosomes and markedly increased cardiac left ventricular dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, injection of plasma exosomes from TAC mice induced left ventricular dysfunction and cardiomyocyte hypertrophy in uninjured mice without TAC. On the contrary, treatment of tipifarnib in TAC mice reduced circulating exosomes to baseline and remarkably improved left ventricular functions, hypertrophy, and fibrosis. Tipifarnib treatment also drastically altered the miRNA profile of circulating post-TAC exosomes, including miR 331-5p, which was highly downregulated both in TAC circulating exosomes and in TAC cardiac tissue. Mechanistically, miR 331-5p is crucial for inhibiting the fibroblast-to-myofibroblast transition by targeting HOXC8, a critical regulator of fibrosis. Tipifarnib treatment in TAC mice upregulated the expression of miR 331-5p that acts as a potent repressor for one of the fibrotic mechanisms mediated by HOXC8.</p><p><strong>Conclusions: </strong>Our study underscores the pathological role of exosomes in HF and fibrosis in response to pressure overload. Tipifarnib-mediated inhibition of exosome biogenesis and cargo sorting may serve as a viable strategy to prevent progressive cardiac remodeling in HF.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"280-297"},"PeriodicalIF":16.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11223950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141283086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial.","authors":"Alastair J S Webb, Jacqueline S Birks, Karolina A Feakins, Amy Lawson, Jesse Dawson, Alexander M K Rothman, David J Werring, Osian Llwyd, Catriona R Stewart, James Thomas","doi":"10.1161/CIRCRESAHA.124.324327","DOIUrl":"10.1161/CIRCRESAHA.124.324327","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Vascular cognitive impairment due to cerebral small vessel disease is associated with cerebral pulsatility, white matter hypoperfusion, and reduced cerebrovascular reactivity (CVR), and is potentially improved by endothelium-targeted drugs such as cilostazol. Whether sildenafil, a phosphodiesterase-5 inhibitor, improves cerebrovascular dysfunction is unknown.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;OxHARP trial (Oxford Haemodynamic Adaptation to Reduce Pulsatility) was a double-blind, randomized, placebo-controlled, 3-way crossover trial after nonembolic cerebrovascular events with mild-moderate white matter hyperintensities (WMH), the most prevalent manifestation of cerebral small vessel disease. The primary outcome assessed the superiority of 3 weeks of sildenafil 50 mg thrice daily versus placebo (mixed-effect linear models) on middle cerebral artery pulsatility, derived from peak systolic and end-diastolic velocities (transcranial ultrasound), with noninferiority to cilostazol 100 mg twice daily. Secondary end points included the following: cerebrovascular reactivity during inhalation of air, 4% and 6% CO&lt;sub&gt;2&lt;/sub&gt; on transcranial ultrasound (transcranial ultrasound-CVR); blood oxygen-level dependent-magnetic resonance imaging within WMH (CVR-WMH) and normal-appearing white matter (CVR-normal-appearing white matter); cerebral perfusion by arterial spin labeling (magnetic resonance imaging pseudocontinuous arterial spin labeling); and resistance by cerebrovascular conductance. Adverse effects were compared by Cochran Q.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In 65/75 (87%) patients (median, 70 years;79% male) with valid primary outcome data, cerebral pulsatility was unchanged on sildenafil versus placebo (0.02, -0.01 to 0.05; &lt;i&gt;P&lt;/i&gt;=0.18), or versus cilostazol (-0.01, -0.04 to 0.02; &lt;i&gt;P&lt;/i&gt;=0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; &lt;i&gt;P&lt;/i&gt;&lt;0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; &lt;i&gt;P&lt;/i&gt;=0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; &lt;i&gt;P&lt;/i&gt;=0.007), CVR-WMH (0.07, 0-0.14; &lt;i&gt;P&lt;/i&gt;=0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; &lt;i&gt;P&lt;/i&gt;=0.048), perfusion (WMH: 1.82 mL/100 g per minute, 0.5-3.15; &lt;i&gt;P&lt;/i&gt;=0.008; and normal-appearing white matter, 2.12, 0.66-3.6; &lt;i&gt;P&lt;/i&gt;=0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; &lt;i&gt;P&lt;/i&gt;=4.9×10&lt;sup&gt;-8&lt;/sup&gt;; cilostazol-placebo, 0.06, 0.03-0.09; &lt;i&gt;P&lt;/i&gt;=5.1×10&lt;sup&gt;-5&lt;/sup&gt;). Both drugs increased headaches (&lt;i&gt;P&lt;/i&gt;=1.1×10&lt;sup&gt;-4&lt;/sup&gt;), while cilostazol increased moderate-severe diarrhea (&lt;i&gt;P&lt;/i&gt;=0.013).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Sildenafil did not reduce pulsatility but increased cerebrovascular reactivity and perfusion. Sildenafil merits further study to determine whether it prevents the clinical sequelae of small vessel disease.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Registration: &lt;/strong&gt;URL: https://www.clinicaltrials.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"320-331"},"PeriodicalIF":16.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11227301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141237034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"\"Tip\" the Scale of Cardiac Repair via Reducing Pathological Extracellular Vesicles.","authors":"Zhang Yue, Ke Cheng","doi":"10.1161/CIRCRESAHA.124.324955","DOIUrl":"10.1161/CIRCRESAHA.124.324955","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 2","pages":"298-300"},"PeriodicalIF":16.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial Structure and Function in Human Heart Failure.","authors":"Antentor Hinton, Steven M Claypool, Kit Neikirk, Nanami Senoo, Celestine N Wanjalla, Annet Kirabo, Clintoria R Williams","doi":"10.1161/CIRCRESAHA.124.323800","DOIUrl":"10.1161/CIRCRESAHA.124.323800","url":null,"abstract":"<p><p>Despite clinical and scientific advancements, heart failure is the major cause of morbidity and mortality worldwide. Both mitochondrial dysfunction and inflammation contribute to the development and progression of heart failure. Although inflammation is crucial to reparative healing following acute cardiomyocyte injury, chronic inflammation damages the heart, impairs function, and decreases cardiac output. Mitochondria, which comprise one third of cardiomyocyte volume, may prove a potential therapeutic target for heart failure. Known primarily for energy production, mitochondria are also involved in other processes including calcium homeostasis and the regulation of cellular apoptosis. Mitochondrial function is closely related to morphology, which alters through mitochondrial dynamics, thus ensuring that the energy needs of the cell are met. However, in heart failure, changes in substrate use lead to mitochondrial dysfunction and impaired myocyte function. This review discusses mitochondrial and cristae dynamics, including the role of the mitochondria contact site and cristae organizing system complex in mitochondrial ultrastructure changes. Additionally, this review covers the role of mitochondria-endoplasmic reticulum contact sites, mitochondrial communication via nanotunnels, and altered metabolite production during heart failure. We highlight these often-neglected factors and promising clinical mitochondrial targets for heart failure.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 2","pages":"372-396"},"PeriodicalIF":16.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11225798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imbalance of APOB Lipoproteins and Large HDL in Type 1 Diabetes Drives Atherosclerosis.","authors":"Vishal Kothari, Tse W W Ho, Ainara G Cabodevilla, Yi He, Farah Kramer, Masami Shimizu-Albergine, Jenny E Kanter, Janet Snell-Bergeon, Edward A Fisher, Baohai Shao, Jay W Heinecke, Jacob O Wobbrock, Warren L Lee, Ira J Goldberg, Tomas Vaisar, Karin E Bornfeldt","doi":"10.1161/CIRCRESAHA.123.323100","DOIUrl":"10.1161/CIRCRESAHA.123.323100","url":null,"abstract":"<p><strong>Background: </strong>Individuals with type 1 diabetes (T1D) generally have normal or even higher HDL (high-density lipoprotein)-cholesterol levels than people without diabetes yet are at increased risk for atherosclerotic cardiovascular disease (CVD). Human HDL is a complex mixture of particles that can vary in cholesterol content by >2-fold. To investigate if specific HDL subspecies contribute to the increased atherosclerosis associated with T1D, we created mouse models of T1D that exhibit human-like HDL subspecies. We also measured HDL subspecies and their association with incident CVD in a cohort of people with T1D.</p><p><strong>Methods: </strong>We generated LDL receptor-deficient (<i>Ldlr</i>^<i>-/-</i>) mouse models of T1D expressing human APOA1 (apolipoprotein A1). <i>Ldlr</i>^<i>-/-</i><i>APOA1</i>^<i>Tg</i> mice exhibited the main human HDL subspecies. We also generated <i>Ldlr</i>^<i>-/-</i><i>APOA1</i>^<i>Tg</i> T1D mice expressing CETP (cholesteryl ester transfer protein), which had lower concentrations of large HDL subspecies versus mice not expressing CETP. HDL particle concentrations and sizes and proteins involved in lipoprotein metabolism were measured by calibrated differential ion mobility analysis and targeted mass spectrometry in the mouse models of T1D and in a cohort of individuals with T1D. Endothelial transcytosis was analyzed by total internal reflection fluorescence microscopy.</p><p><strong>Results: </strong>Diabetic <i>Ldlr</i>^<i>-/-</i><i>APOA1</i>^<i>Tg</i> mice were severely hyperglycemic and hyperlipidemic and had markedly elevated plasma APOB levels versus nondiabetic littermates but were protected from the proatherogenic effects of diabetes. Diabetic <i>Ldlr</i>^<i>-/-</i><i>APOA1</i>^<i>Tg</i> mice expressing CETP lost the atheroprotective effect and had increased lesion necrotic core areas and APOB accumulation, despite having lower plasma APOB levels. The detrimental effects of low concentrations of larger HDL particles in diabetic mice expressing CETP were not explained by reduced cholesterol efflux. Instead, large HDL was more effective than small HDL in preventing endothelial transcytosis of LDL mediated by scavenger receptor class B type 1. Finally, in humans with T1D, increased concentrations of larger HDL particles relative to APOB100 negatively predicted incident CVD independently of HDL-cholesterol levels.</p><p><strong>Conclusions: </strong>Our results suggest that the balance between APOB lipoproteins and the larger HDL subspecies contributes to atherosclerosis progression and incident CVD in the setting of T1D and that larger HDLs exert atheroprotective effects on endothelial cells rather than by promoting macrophage cholesterol efflux.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"335-349"},"PeriodicalIF":16.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11223987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}