Pub Date : 2024-09-01Epub Date: 2024-08-21DOI: 10.1161/ATVBAHA.124.321392
Sascha N Goonewardena, Qinzhong Chen, Ashley M Tate, Olga G Grushko, Dilna Damodaran Puthiya Veettil, Pennelope K Blakely, Salim S Hayek, David J Pinsky, Robert S Rosenson
{"title":"Response by Goonewardena et al to Letter Regarding Article, \"Monocyte-Mediated Thrombosis Linked to Circulating Tissue Factor and Immune Paralysis in COVID-19\".","authors":"Sascha N Goonewardena, Qinzhong Chen, Ashley M Tate, Olga G Grushko, Dilna Damodaran Puthiya Veettil, Pennelope K Blakely, Salim S Hayek, David J Pinsky, Robert S Rosenson","doi":"10.1161/ATVBAHA.124.321392","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.321392","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016227","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}
Pub Date : 2024-09-01Epub Date: 2024-08-01DOI: 10.1161/ATVBAHA.124.321164
Richa Banerjee, Luz A Knauer, Drishya Iyer, Sara E Barlow, Hanan Shalaby, Razieh Dehghan, Joshua P Scallan, Ying Yang
Background: Lymphatic valves are specialized structures in collecting lymphatic vessels and are crucial for preventing retrograde lymph flow. Mutations in valve-forming genes have been clinically implicated in the pathology of congenital lymphedema. Lymphatic valves form when oscillatory shear stress from lymph flow signals through the PI3K/AKT pathway to promote the transcription of valve-forming genes that trigger the growth and maintenance of lymphatic valves. Conventionally, in many cell types, AKT is phosphorylated at Ser473 by the mTORC2 (mammalian target of rapamycin complex 2). However, mTORC2 has not yet been implicated in lymphatic valve formation.
Methods: In vivo and in vitro techniques were used to investigate the role of Rictor, a critical component of mTORC2, in lymphatic endothelium.
Results: Here, we showed that embryonic and postnatal lymphatic deletion of Rictor, a critical component of mTORC2, led to a significant decrease in lymphatic valves and prevented the maturation of collecting lymphatic vessels. RICTOR knockdown in human dermal lymphatic endothelial cells not only reduced the level of activated AKT and the expression of valve-forming genes under no-flow conditions but also abolished the upregulation of AKT activity and valve-forming genes in response to oscillatory shear stress. We further showed that the AKT target, FOXO1 (forkhead box protein O1), a repressor of lymphatic valve formation, had increased nuclear activity in Rictor knockout mesenteric lymphatic endothelial cells in vivo. Deletion of Foxo1 in Rictor knockout mice restored the number of valves to control levels in lymphatic vessels of the ear and mesentery.
Conclusions: Our work identifies a novel role for RICTOR in the mechanotransduction signaling pathway, wherein it activates AKT and prevents the nuclear accumulation of the valve repressor, FOXO1, which ultimately enables the formation and maintenance of lymphatic valves.
{"title":"Rictor, an mTORC2 Protein, Regulates Murine Lymphatic Valve Formation Through the AKT-FOXO1 Signaling.","authors":"Richa Banerjee, Luz A Knauer, Drishya Iyer, Sara E Barlow, Hanan Shalaby, Razieh Dehghan, Joshua P Scallan, Ying Yang","doi":"10.1161/ATVBAHA.124.321164","DOIUrl":"10.1161/ATVBAHA.124.321164","url":null,"abstract":"<p><strong>Background: </strong>Lymphatic valves are specialized structures in collecting lymphatic vessels and are crucial for preventing retrograde lymph flow. Mutations in valve-forming genes have been clinically implicated in the pathology of congenital lymphedema. Lymphatic valves form when oscillatory shear stress from lymph flow signals through the PI3K/AKT pathway to promote the transcription of valve-forming genes that trigger the growth and maintenance of lymphatic valves. Conventionally, in many cell types, AKT is phosphorylated at Ser473 by the mTORC2 (mammalian target of rapamycin complex 2). However, mTORC2 has not yet been implicated in lymphatic valve formation.</p><p><strong>Methods: </strong>In vivo and in vitro techniques were used to investigate the role of <i>Rictor</i>, a critical component of mTORC2, in lymphatic endothelium.</p><p><strong>Results: </strong>Here, we showed that embryonic and postnatal lymphatic deletion of <i>Rictor</i>, a critical component of mTORC2, led to a significant decrease in lymphatic valves and prevented the maturation of collecting lymphatic vessels. <i>RICTOR</i> knockdown in human dermal lymphatic endothelial cells not only reduced the level of activated AKT and the expression of valve-forming genes under no-flow conditions but also abolished the upregulation of AKT activity and valve-forming genes in response to oscillatory shear stress. We further showed that the AKT target, FOXO1 (forkhead box protein O1), a repressor of lymphatic valve formation, had increased nuclear activity in <i>Rictor</i> knockout mesenteric lymphatic endothelial cells in vivo. Deletion of <i>Foxo1</i> in <i>Rictor</i> knockout mice restored the number of valves to control levels in lymphatic vessels of the ear and mesentery.</p><p><strong>Conclusions: </strong>Our work identifies a novel role for RICTOR in the mechanotransduction signaling pathway, wherein it activates AKT and prevents the nuclear accumulation of the valve repressor, FOXO1, which ultimately enables the formation and maintenance of lymphatic valves.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11335088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858931","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}
Pub Date : 2024-09-01Epub Date: 2024-07-25DOI: 10.1161/ATVBAHA.124.321110
Takehiro Nakahara, Raita Miyazawa, Yu Iwabuchi, Kai Tonda, Nupoor Narula, H William Strauss, Jagat Narula, Masahiro Jinzaki
Background: Abdominal aortic aneurysms expand over time and increase the risk of fatal ruptures. To predict expansion, the isolated assessment of 18F-fluorodeoxyglucose (FDG) and sodium fluoride (NaF) uptake or calcification volume in aneurysms has been investigated with variability in results. We systematically evaluated whether 18F-FDG and 18F-NaF uptake was predictive of abdominal aortic aneurysm expansion.
Methods: Seventy-four male Sprague-Dawley rat abdominal aortic aneurysm models were imaged using positron emission tomography-computed tomography with 18F-FDG and 18F-NaF at 1, 2, 4, 6, and 8 weeks after CaCl2 or saline stimulation. In the 1-week cohort (n=25), the correlation between 18F-FDG or 18F-NaF uptake and pathological markers was investigated. In the time course cohort (n=49), animals received either atorvastatin, losartan, aldactone, or risedronate to assess the effect of these drugs, and the relationship between aortic size and sequential 18F-FDG and 18F-NaF uptake or calcification volume was examined.
Results: In the 1-week cohort, the maximum standard unit value of 18F-FDG and 18F-NaF uptake correlated with CD68- (r=0.82; P=0.001) and von Kossa staining-positive areas (r=0.89; P<0.001), respectively. In the time course cohort, 18F-FDG and 18F-NaF uptake changed in a time-dependent manner and drugs attenuated this uptake. Specifically, 18F-FDG showed high uptake at weeks 1 and 2, whereas a high 18F-NaF uptake was noted throughout the study period. Atorvastatin and risedronate showed a decreased and increased aortic size, respectively. The final aortic area correlated well with 18F-FDG and 18F-NaF uptake and calcification volume, especially at 1 and 2 weeks (18F-NaF [1 week]: r=0.61, 18F-FDG [2 weeks]: r=0.51, calcification volume [1 week]: r=0.59; P<0.001). Multiple linear regression analysis showed that the combination of these factors predicted the final aortic size, with 18F-NaF uptake at 1 week being the strongest predictor.
Conclusions: The uptake of 18F-NaF and 18F-FDG and the calcification volume at appropriate times correlated with the development of abdominal aortic aneurysms, with 18F-NaF uptake being the strongest predictor.
{"title":"Aortic Uptake of <sup>18</sup>F-NaF and <sup>18</sup>F-FDG and Calcification Predict the Development of Abdominal Aortic Aneurysms and Is Attenuated by Drug Therapy.","authors":"Takehiro Nakahara, Raita Miyazawa, Yu Iwabuchi, Kai Tonda, Nupoor Narula, H William Strauss, Jagat Narula, Masahiro Jinzaki","doi":"10.1161/ATVBAHA.124.321110","DOIUrl":"10.1161/ATVBAHA.124.321110","url":null,"abstract":"<p><strong>Background: </strong>Abdominal aortic aneurysms expand over time and increase the risk of fatal ruptures. To predict expansion, the isolated assessment of <sup>18</sup>F-fluorodeoxyglucose (FDG) and sodium fluoride (NaF) uptake or calcification volume in aneurysms has been investigated with variability in results. We systematically evaluated whether <sup>18</sup>F-FDG and <sup>18</sup>F-NaF uptake was predictive of abdominal aortic aneurysm expansion.</p><p><strong>Methods: </strong>Seventy-four male Sprague-Dawley rat abdominal aortic aneurysm models were imaged using positron emission tomography-computed tomography with <sup>18</sup>F-FDG and <sup>18</sup>F-NaF at 1, 2, 4, 6, and 8 weeks after CaCl<sub>2</sub> or saline stimulation. In the 1-week cohort (n=25), the correlation between <sup>18</sup>F-FDG or <sup>18</sup>F-NaF uptake and pathological markers was investigated. In the time course cohort (n=49), animals received either atorvastatin, losartan, aldactone, or risedronate to assess the effect of these drugs, and the relationship between aortic size and sequential <sup>18</sup>F-FDG and <sup>18</sup>F-NaF uptake or calcification volume was examined.</p><p><strong>Results: </strong>In the 1-week cohort, the maximum standard unit value of <sup>18</sup>F-FDG and <sup>18</sup>F-NaF uptake correlated with CD68- (r=0.82; <i>P</i>=0.001) and von Kossa staining-positive areas (r=0.89; <i>P</i><0.001), respectively. In the time course cohort, <sup>18</sup>F-FDG and <sup>18</sup>F-NaF uptake changed in a time-dependent manner and drugs attenuated this uptake. Specifically, <sup>18</sup>F-FDG showed high uptake at weeks 1 and 2, whereas a high <sup>18</sup>F-NaF uptake was noted throughout the study period. Atorvastatin and risedronate showed a decreased and increased aortic size, respectively. The final aortic area correlated well with <sup>18</sup>F-FDG and <sup>18</sup>F-NaF uptake and calcification volume, especially at 1 and 2 weeks (<sup>18</sup>F-NaF [1 week]: r=0.61, <sup>18</sup>F-FDG [2 weeks]: r=0.51, calcification volume [1 week]: r=0.59; <i>P</i><0.001). Multiple linear regression analysis showed that the combination of these factors predicted the final aortic size, with <sup>18</sup>F-NaF uptake at 1 week being the strongest predictor.</p><p><strong>Conclusions: </strong>The uptake of <sup>18</sup>F-NaF and <sup>18</sup>F-FDG and the calcification volume at appropriate times correlated with the development of abdominal aortic aneurysms, with <sup>18</sup>F-NaF uptake being the strongest predictor.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141756850","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}
Pub Date : 2024-09-01Epub Date: 2024-08-01DOI: 10.1161/ATVBAHA.124.320998
Amandine Chaix, Terry Lin, Bastian Ramms, Roy G Cutler, Tiffani Le, Catherine Lopez, Phuong Miu, Antonio F M Pinto, Alan Saghatelian, Martin P Playford, Nehal N Mehta, Mark P Mattson, Philip Gordts, Joseph L Witztum, Satchidananda Panda
Background: Dyslipidemia increases cardiovascular disease risk, the leading cause of death worldwide. Under time-restricted feeding (TRF), wherein food intake is restricted to a consistent window of <12 hours, weight gain, glucose intolerance, inflammation, dyslipidemia, and hypercholesterolemia are all reduced in mice fed an obesogenic diet. LDLR (low-density lipoprotein receptor) mutations are a major cause of familial hypercholesterolemia and early-onset cardiovascular disease.
Methods: We subjected benchmark preclinical models, mice lacking LDLR-knockout or ApoE knockout to ad libitum feeding of an isocaloric atherogenic diet either ad libitum or 9 hours TRF for up to 13 weeks and assessed disease development, mechanism, and global changes in hepatic gene expression and plasma lipids. In a regression model, a subset of LDLR-knockout mice were ad libitum fed and then subject to TRF.
Results: TRF could significantly attenuate weight gain, hypercholesterolemia, and atherosclerosis in mice lacking the LDLR-knockout mice under experimental conditions of both prevention and regression. In LDLR-knockout mice, increased hepatic expression of genes mediating β-oxidation during fasting is associated with reduced VLDL (very-low-density lipoprotein) secretion and lipid accumulation. Additionally, increased sterol catabolism coupled with fecal loss of cholesterol and bile acids contributes to the atheroprotective effect of TRF. Finally, TRF alone or combined with a cholesterol-free diet can reduce atherosclerosis in LDLR-knockout mice. However, mice lacking ApoE, which is an important protein for hepatic lipoprotein reuptake do not respond to TRF.
Conclusions: In a preclinical animal model, TRF is effective in both the prevention and regression of atherosclerosis in LDLR knockout mice. The results suggest TRF alone or in combination with a low-cholesterol diet can be a lifestyle intervention for reducing cardiovascular disease risk in humans.
{"title":"Time-Restricted Feeding Reduces Atherosclerosis in LDLR KO Mice but Not in ApoE Knockout Mice.","authors":"Amandine Chaix, Terry Lin, Bastian Ramms, Roy G Cutler, Tiffani Le, Catherine Lopez, Phuong Miu, Antonio F M Pinto, Alan Saghatelian, Martin P Playford, Nehal N Mehta, Mark P Mattson, Philip Gordts, Joseph L Witztum, Satchidananda Panda","doi":"10.1161/ATVBAHA.124.320998","DOIUrl":"10.1161/ATVBAHA.124.320998","url":null,"abstract":"<p><strong>Background: </strong>Dyslipidemia increases cardiovascular disease risk, the leading cause of death worldwide. Under time-restricted feeding (TRF), wherein food intake is restricted to a consistent window of <12 hours, weight gain, glucose intolerance, inflammation, dyslipidemia, and hypercholesterolemia are all reduced in mice fed an obesogenic diet. LDLR (low-density lipoprotein receptor) mutations are a major cause of familial hypercholesterolemia and early-onset cardiovascular disease.</p><p><strong>Methods: </strong>We subjected benchmark preclinical models, mice lacking LDLR-knockout or ApoE knockout to ad libitum feeding of an isocaloric atherogenic diet either ad libitum or 9 hours TRF for up to 13 weeks and assessed disease development, mechanism, and global changes in hepatic gene expression and plasma lipids. In a regression model, a subset of LDLR-knockout mice were ad libitum fed and then subject to TRF.</p><p><strong>Results: </strong>TRF could significantly attenuate weight gain, hypercholesterolemia, and atherosclerosis in mice lacking the LDLR-knockout mice under experimental conditions of both prevention and regression. In LDLR-knockout mice, increased hepatic expression of genes mediating β-oxidation during fasting is associated with reduced VLDL (very-low-density lipoprotein) secretion and lipid accumulation. Additionally, increased sterol catabolism coupled with fecal loss of cholesterol and bile acids contributes to the atheroprotective effect of TRF. Finally, TRF alone or combined with a cholesterol-free diet can reduce atherosclerosis in LDLR-knockout mice. However, mice lacking ApoE, which is an important protein for hepatic lipoprotein reuptake do not respond to TRF.</p><p><strong>Conclusions: </strong>In a preclinical animal model, TRF is effective in both the prevention and regression of atherosclerosis in LDLR knockout mice. The results suggest TRF alone or in combination with a low-cholesterol diet can be a lifestyle intervention for reducing cardiovascular disease risk in humans.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858933","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}
Pub Date : 2024-08-29DOI: 10.1161/ATVBAHA.124.321087
Karlijn B Rombouts, Tara A R van Merrienboer, Alex A Henneman, Jaco C Knol, Thang V Pham, Sander R Piersma, Connie R Jimenez, Natalija Bogunovic, Jolanda van der Velden, Kak Khee Yeung
Background: Abdominal aortic aneurysm (AAA) is characterized by weakening and dilatation of the aortic wall in the abdomen. The aim of this study was to gain insight into cell-specific mechanisms involved in AAA pathophysiology by analyzing the (phospho)proteome of vascular smooth muscle cells derived from patients with AAA compared with those of healthy donors.
Methods: A (phospho)proteomics analysis based on tandem mass spectrometry was performed on vascular smooth muscle cells derived from patients with AAA (n=24) and healthy, control individuals (C-SMC, n=8). Following protein identification and quantification using MaxQuant, integrative inferred kinase activity analysis was used to calculate kinase activity scores.
Results: Expression differences between vascular smooth muscle cells derived from patients with AAA and healthy, control individuals were predominantly found in proteins involved in ECM (extracellular matrix) remodeling (THSD4 [thrombospondin type-1 domain-containing protein 4] and ADAMTS1 [A disintegrin and metalloproteinase with thrombospondin motifs 1]), energy metabolism (GYS1 [glycogen synthase 1] and PCK2 [phosphoenolpyruvate carboxykinase 2, mitochondrial]), and contractility (CACNA2D1 [calcium voltage-dependent channel subunit α-2/δ-1] and TPM1 [tropomyosin α-1 chain]). Phosphorylation patterns on proteins related to actin cytoskeleton organization dominated the phosphoproteome of vascular smooth muscle cells derived from patients with AAA . Besides, phosphorylation changes on proteins related to energy metabolism (GYS1), contractility (PARVA [α-parvin], PPP1R12A [protein phosphatase 1 regulatory subunit 12A], and CALD1 [caldesmon 1]), and intracellular communication (GJA1 [gap junction α-1 protein]) were seen. Kinase activity of NUAK1 (NUAK family SNF1-like kinase 1), FYN (tyrosine-protein kinase Fyn), MAPK7 (mitogen-activated protein kinase 7), and STK10 (serine/threonine kinase 10) was different in vascular smooth muscle cells derived from patients with AAA compared with those from healthy, control individuals.
Conclusions: This study revealed changes in expression and phosphorylation levels of proteins involved in various processes responsible for AAA progression and development (eg, energy metabolism, ECM remodeling, actin cytoskeleton organization, contractility, intracellular communication, and cell adhesion). These newly identified proteins, phosphosites, and related kinases provide further insight into the underlying mechanism of vascular smooth muscle cell dysfunction within the aneurysmal wall. Our omics data thereby offer the opportunity to study the relevance, either as drug target or biomarker, of these proteins in AAA development.
{"title":"Insight in the (Phospho)proteome of Vascular Smooth Muscle Cells Derived From Patients With Abdominal Aortic Aneurysm Reveals Novel Disease Mechanisms.","authors":"Karlijn B Rombouts, Tara A R van Merrienboer, Alex A Henneman, Jaco C Knol, Thang V Pham, Sander R Piersma, Connie R Jimenez, Natalija Bogunovic, Jolanda van der Velden, Kak Khee Yeung","doi":"10.1161/ATVBAHA.124.321087","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.321087","url":null,"abstract":"<p><strong>Background: </strong>Abdominal aortic aneurysm (AAA) is characterized by weakening and dilatation of the aortic wall in the abdomen. The aim of this study was to gain insight into cell-specific mechanisms involved in AAA pathophysiology by analyzing the (phospho)proteome of vascular smooth muscle cells derived from patients with AAA compared with those of healthy donors.</p><p><strong>Methods: </strong>A (phospho)proteomics analysis based on tandem mass spectrometry was performed on vascular smooth muscle cells derived from patients with AAA (n=24) and healthy, control individuals (C-SMC, n=8). Following protein identification and quantification using MaxQuant, integrative inferred kinase activity analysis was used to calculate kinase activity scores.</p><p><strong>Results: </strong>Expression differences between vascular smooth muscle cells derived from patients with AAA and healthy, control individuals were predominantly found in proteins involved in ECM (extracellular matrix) remodeling (THSD4 [thrombospondin type-1 domain-containing protein 4] and ADAMTS1 [A disintegrin and metalloproteinase with thrombospondin motifs 1]), energy metabolism (GYS1 [glycogen synthase 1] and PCK2 [phosphoenolpyruvate carboxykinase 2, mitochondrial]), and contractility (CACNA2D1 [calcium voltage-dependent channel subunit α-2/δ-1] and TPM1 [tropomyosin α-1 chain]). Phosphorylation patterns on proteins related to actin cytoskeleton organization dominated the phosphoproteome of vascular smooth muscle cells derived from patients with AAA . Besides, phosphorylation changes on proteins related to energy metabolism (GYS1), contractility (PARVA [α-parvin], PPP1R12A [protein phosphatase 1 regulatory subunit 12A], and CALD1 [caldesmon 1]), and intracellular communication (GJA1 [gap junction α-1 protein]) were seen. Kinase activity of NUAK1 (NUAK family SNF1-like kinase 1), FYN (tyrosine-protein kinase Fyn), MAPK7 (mitogen-activated protein kinase 7), and STK10 (serine/threonine kinase 10) was different in vascular smooth muscle cells derived from patients with AAA compared with those from healthy, control individuals.</p><p><strong>Conclusions: </strong>This study revealed changes in expression and phosphorylation levels of proteins involved in various processes responsible for AAA progression and development (eg, energy metabolism, ECM remodeling, actin cytoskeleton organization, contractility, intracellular communication, and cell adhesion). These newly identified proteins, phosphosites, and related kinases provide further insight into the underlying mechanism of vascular smooth muscle cell dysfunction within the aneurysmal wall. Our omics data thereby offer the opportunity to study the relevance, either as drug target or biomarker, of these proteins in AAA development.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103906","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}
Pub Date : 2024-08-29DOI: 10.1161/ATVBAHA.124.321555
Naoki Kiyota, Tuncer Onay, Phoebe Leeaw, Pan Liu, Dilip K Deb, Benjamin R Thomson, Ayellet V Segrè, Janey L Wiggs, Susan E Quaggin
Background: The ANGPT (angiopoietin)-TEK (tyrosine kinase, endothelial) vascular signaling pathway plays a key role in the formation of Schlemm canal, and loss-of-function mutations in the TEK or ANGPT1 gene are associated with primary congenital glaucoma in children. In genome-wide association studies, an association was identified between protection from primary open-angle glaucoma and the single-nucleotide polymorphism rs76020419 (G>T), located within a predicted miR-145-binding site in the 3' untranslated region of ANGPT2. To date, the functional impact of this variant in the anterior chamber of the eye remains largely unexplored.
Methods: MT (mutant) mice harboring an orthologous rs76020419 minor allele (T) were generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9). Plasma and tissue samples, including eyes, were collected, and ANGPT2 expression was quantified using ELISA. Anterior segments from eyes were collected from WT (wild-type) and MT mice, and Schlemm canal area was quantified.
Results: In the MT group, higher ANGPT2 concentrations were observed in the plasma, lungs, kidneys, and eyes (P=0.0212, P<0.001, P=0.0815, and P=0.0215, respectively). Additionally, the Schlemm canal was larger in MT mice compared with WT mice (P=0.0430).
Conclusions: The rs76020419 minor allele (T) is associated with increased levels of ANGPT2 and a larger Schlemm canal in mice. These findings suggest a potential protective mechanism in glaucoma.
{"title":"Glaucoma-Protective Human Single-Nucleotide Polymorphism in the <i>Angpt2</i> Locus Increased ANGPT2 Expression and Schlemm Canal Area in Mice.","authors":"Naoki Kiyota, Tuncer Onay, Phoebe Leeaw, Pan Liu, Dilip K Deb, Benjamin R Thomson, Ayellet V Segrè, Janey L Wiggs, Susan E Quaggin","doi":"10.1161/ATVBAHA.124.321555","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.321555","url":null,"abstract":"<p><strong>Background: </strong>The ANGPT (angiopoietin)-TEK (tyrosine kinase, endothelial) vascular signaling pathway plays a key role in the formation of Schlemm canal, and loss-of-function mutations in the <i>TEK</i> or <i>ANGPT1</i> gene are associated with primary congenital glaucoma in children. In genome-wide association studies, an association was identified between protection from primary open-angle glaucoma and the single-nucleotide polymorphism rs76020419 (G>T), located within a predicted <i>miR-145</i>-binding site in the 3' untranslated region of <i>ANGPT2</i>. To date, the functional impact of this variant in the anterior chamber of the eye remains largely unexplored.</p><p><strong>Methods: </strong>MT (mutant) mice harboring an orthologous rs76020419 minor allele (T) were generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9). Plasma and tissue samples, including eyes, were collected, and ANGPT2 expression was quantified using ELISA. Anterior segments from eyes were collected from WT (wild-type) and MT mice, and Schlemm canal area was quantified.</p><p><strong>Results: </strong>In the MT group, higher ANGPT2 concentrations were observed in the plasma, lungs, kidneys, and eyes (<i>P</i>=0.0212, <i>P</i><0.001, <i>P</i>=0.0815, and <i>P</i>=0.0215, respectively). Additionally, the Schlemm canal was larger in MT mice compared with WT mice (<i>P</i>=0.0430).</p><p><strong>Conclusions: </strong>The rs76020419 minor allele (T) is associated with increased levels of ANGPT2 and a larger Schlemm canal in mice. These findings suggest a potential protective mechanism in glaucoma.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103904","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}
Pub Date : 2024-08-29DOI: 10.1161/ATVBAHA.123.320615
Tobias Feige, Agnes Bosbach, Kim J Krott, Joscha Mulorz, Madhumita Chatterjee, Julia Ortscheid, Evelyn Krüger, Irena Krüger, Niloofar Salehzadeh, Silvia Goebel, Wiebke Ibing, Maria Grandoch, Götz Münch, Markus U Wagenhäuser, Hubert Schelzig, Margitta Elvers
Background: Platelets play an important role in cardiovascular and cerebrovascular diseases. Abdominal aortic aneurysm (AAA) is a highly lethal, atherosclerosis-related disease with characteristic features of progressive dilatation of the abdominal aorta and degradation of the vessel wall, accompanied by chronic inflammation. Platelet activation and procoagulant activity play a decisive role in the AAA pathology as they might trigger AAA development in both mice and humans.
Methods: The present study investigated the impact of the major platelet collagen receptor GP (platelet glycoprotein) VI in pathophysiological processes underlying AAA initiation and progression. For experimental AAA induction in mice, PPE (porcine pancreatic elastase) and the external PPE model were used.
Results: Genetic deletion of GP VI offered protection of mice against aortic diameter expansion in experimental AAA. Mechanistically, GP VI deficiency resulted in decreased inflammation with reduced infiltration of neutrophils and platelets into the aortic wall. Furthermore, remodeling of the aortic wall was improved in the absence of GP VI, as indicated by reduced MMP (matrix metalloproteinase)-2/9 and OPN (osteopontin) plasma levels and an enhanced α-SMA (α-smooth muscle actin) content within the aortic wall, accompanied by reduced cell apoptosis. Consequently, an elevation in intima/media thickness and elastin content was observed in GP VI-deficient PPE mice, resulting in a significantly reduced aortic diameter expansion and reduced aneurysm incidence. In patients with AAA, enhanced plasma levels of soluble GP VI and fibrin, as well as fibrin accumulation within the intraluminal thrombus might serve as new biomarkers to detect AAA early. Moreover, we hypothesize that GP VI might play a role in procoagulant activity and thrombus stabilization via binding to fibrin.
Conclusions: In conclusion, our results emphasize the potential need for a GP VI-targeted antiplatelet therapy to reduce AAA initiation and progression, as well as to protect patients with AAA from aortic rupture.
背景:血小板在心脑血管疾病中发挥着重要作用。腹主动脉瘤(AAA)是一种致死率极高的动脉粥样硬化相关疾病,其特征是腹主动脉进行性扩张和血管壁退化,并伴有慢性炎症。血小板活化和促凝血活性在 AAA 病理学中起着决定性作用,因为它们可能诱发小鼠和人类 AAA 的发生:本研究探讨了主要血小板胶原受体 GP(血小板糖蛋白)VI 在 AAA 发生和发展的病理生理过程中的影响。在小鼠实验性AAA诱导中,使用了PPE(猪胰弹性蛋白酶)和外部PPE模型:结果:基因缺失 GP VI 可保护小鼠免受实验性 AAA 中主动脉直径扩张的影响。从机理上讲,GP VI 的缺失导致中性粒细胞和血小板渗入主动脉壁的炎症减少。此外,在 GP VI 缺乏的情况下,主动脉壁的重塑也得到了改善,这表现在 MMP(基质金属蛋白酶)-2/9 和 OPN(骨生成素)血浆水平降低,主动脉壁内的α-SMA(α-平滑肌肌动蛋白)含量增加,同时细胞凋亡减少。因此,在 GP VI 缺陷的 PPE 小鼠中观察到了内膜/中膜厚度和弹性蛋白含量的增加,从而显著减少了主动脉直径的扩张,降低了动脉瘤的发病率。在 AAA 患者中,血浆中可溶性 GP VI 和纤维蛋白水平的升高以及管腔内血栓中纤维蛋白的积聚可作为早期发现 AAA 的新生物标志物。此外,我们假设 GP VI 可能通过与纤维蛋白结合,在促凝活性和血栓稳定方面发挥作用:总之,我们的研究结果强调了对 GP VI 靶向抗血小板疗法的潜在需求,以减少 AAA 的发生和发展,并保护 AAA 患者免受主动脉破裂的伤害。
{"title":"GP VI-Mediated Platelet Activation and Procoagulant Activity Aggravate Inflammation and Aortic Wall Remodeling in Abdominal Aortic Aneurysm.","authors":"Tobias Feige, Agnes Bosbach, Kim J Krott, Joscha Mulorz, Madhumita Chatterjee, Julia Ortscheid, Evelyn Krüger, Irena Krüger, Niloofar Salehzadeh, Silvia Goebel, Wiebke Ibing, Maria Grandoch, Götz Münch, Markus U Wagenhäuser, Hubert Schelzig, Margitta Elvers","doi":"10.1161/ATVBAHA.123.320615","DOIUrl":"https://doi.org/10.1161/ATVBAHA.123.320615","url":null,"abstract":"<p><strong>Background: </strong>Platelets play an important role in cardiovascular and cerebrovascular diseases. Abdominal aortic aneurysm (AAA) is a highly lethal, atherosclerosis-related disease with characteristic features of progressive dilatation of the abdominal aorta and degradation of the vessel wall, accompanied by chronic inflammation. Platelet activation and procoagulant activity play a decisive role in the AAA pathology as they might trigger AAA development in both mice and humans.</p><p><strong>Methods: </strong>The present study investigated the impact of the major platelet collagen receptor GP (platelet glycoprotein) VI in pathophysiological processes underlying AAA initiation and progression. For experimental AAA induction in mice, PPE (porcine pancreatic elastase) and the external PPE model were used.</p><p><strong>Results: </strong>Genetic deletion of GP VI offered protection of mice against aortic diameter expansion in experimental AAA. Mechanistically, GP VI deficiency resulted in decreased inflammation with reduced infiltration of neutrophils and platelets into the aortic wall. Furthermore, remodeling of the aortic wall was improved in the absence of GP VI, as indicated by reduced MMP (matrix metalloproteinase)-2/9 and OPN (osteopontin) plasma levels and an enhanced α-SMA (α-smooth muscle actin) content within the aortic wall, accompanied by reduced cell apoptosis. Consequently, an elevation in intima/media thickness and elastin content was observed in GP VI-deficient PPE mice, resulting in a significantly reduced aortic diameter expansion and reduced aneurysm incidence. In patients with AAA, enhanced plasma levels of soluble GP VI and fibrin, as well as fibrin accumulation within the intraluminal thrombus might serve as new biomarkers to detect AAA early. Moreover, we hypothesize that GP VI might play a role in procoagulant activity and thrombus stabilization via binding to fibrin.</p><p><strong>Conclusions: </strong>In conclusion, our results emphasize the potential need for a GP VI-targeted antiplatelet therapy to reduce AAA initiation and progression, as well as to protect patients with AAA from aortic rupture.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103905","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}
Pub Date : 2024-08-22DOI: 10.1161/ATVBAHA.124.321131
Sean X Gu, Brian S Marcus, Vivian W Gu, Adarsh P Varghese, John Hwa, E Vincent S Faustino
Background: Congenital heart disease (CHD) is a group of complex heart defects associated with hematologic abnormalities, including increased risk of thrombotic and bleeding events. Past studies have observed evidence of platelet hyperreactivity, while other studies showed decreased platelet activation in patients with CHD. The goal of this study was to develop a mass spectrometry approach to characterize single platelets in infants with CHD and identify potential etiology for such discrepant results.
Methods: We enrolled 19 infants with CHD along with 21 non-CHD controls at Yale New Haven Children's Heart Center. A single-cell high-dimensional mass cytometry method was developed to quantitatively interrogate platelet surface markers in whole blood. Additionally, plasma cytokine analysis was performed through a multiplexed panel of 52 vascular and inflammatory markers to assess for platelet releasates.
Results: We found that infants with CHD had significant differences in platelet activation and functional markers by mass cytometry compared with non-CHD controls. Based on cell surface markers, we classified the platelets into 8 subpopulations (P0 to P7). Distinct subpopulations of platelets (P1, P4, and P5) exhibiting decreased aggregatory phenotype but altered secretory phenotypes were also identified and found to be more abundant in the blood of infants with CHD. Electron microscopy identified increased proportion of hypogranular platelets in CHD. Moreover, cytokine analysis demonstrated an overall increase in plasma cytokines and biomarkers in CHD, including IL (interleukin)-6, IL-8, IL-27, RANTES, and VWF (von Willebrand factor), which are expressed in platelet granules and can be released upon activation.
Conclusions: We developed a robust mass cytometry approach to identify platelet phenotypic heterogeneity. Infants with CHD had alterations in distinct subpopulations of platelets with overall reduced aggregatory phenotype and secretory dysfunction. These findings suggest that platelets in infants with CHD may be exhausted due to persistent stimulation and may explain both bleeding and thrombotic vascular complications associated with CHD.
{"title":"High-Dimensional Single-Cell Mass Cytometry Demonstrates Differential Platelet Functional Phenotypes in Infants With Congenital Heart Disease.","authors":"Sean X Gu, Brian S Marcus, Vivian W Gu, Adarsh P Varghese, John Hwa, E Vincent S Faustino","doi":"10.1161/ATVBAHA.124.321131","DOIUrl":"10.1161/ATVBAHA.124.321131","url":null,"abstract":"<p><strong>Background: </strong>Congenital heart disease (CHD) is a group of complex heart defects associated with hematologic abnormalities, including increased risk of thrombotic and bleeding events. Past studies have observed evidence of platelet hyperreactivity, while other studies showed decreased platelet activation in patients with CHD. The goal of this study was to develop a mass spectrometry approach to characterize single platelets in infants with CHD and identify potential etiology for such discrepant results.</p><p><strong>Methods: </strong>We enrolled 19 infants with CHD along with 21 non-CHD controls at Yale New Haven Children's Heart Center. A single-cell high-dimensional mass cytometry method was developed to quantitatively interrogate platelet surface markers in whole blood. Additionally, plasma cytokine analysis was performed through a multiplexed panel of 52 vascular and inflammatory markers to assess for platelet releasates.</p><p><strong>Results: </strong>We found that infants with CHD had significant differences in platelet activation and functional markers by mass cytometry compared with non-CHD controls. Based on cell surface markers, we classified the platelets into 8 subpopulations (P0 to P7). Distinct subpopulations of platelets (P1, P4, and P5) exhibiting decreased aggregatory phenotype but altered secretory phenotypes were also identified and found to be more abundant in the blood of infants with CHD. Electron microscopy identified increased proportion of hypogranular platelets in CHD. Moreover, cytokine analysis demonstrated an overall increase in plasma cytokines and biomarkers in CHD, including IL (interleukin)-6, IL-8, IL-27, RANTES, and VWF (von Willebrand factor), which are expressed in platelet granules and can be released upon activation.</p><p><strong>Conclusions: </strong>We developed a robust mass cytometry approach to identify platelet phenotypic heterogeneity. Infants with CHD had alterations in distinct subpopulations of platelets with overall reduced aggregatory phenotype and secretory dysfunction. These findings suggest that platelets in infants with CHD may be exhausted due to persistent stimulation and may explain both bleeding and thrombotic vascular complications associated with CHD.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016223","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}
Pub Date : 2024-08-15DOI: 10.1161/ATVBAHA.124.321104
Emily Janus-Bell, Nicolas Receveur, Luc Mercier, Clarisse Mouriaux, Stéphanie Magnenat, Jochen Reiser, François Lanza, Béatrice Hechler, Benoit Ho-Tin-Noé, Pierre H Mangin
Background: Platelets prevent bleeding in a variety of inflammatory settings, the adhesion receptors and activation pathways involved being highly context-dependent and functionally redundant. In some situations, platelets recruited to inflammatory sites act independently of aggregation. The mechanisms underlying stable platelet adhesion in inflamed microvessels remain incompletely understood, in particular, whether and if so, how β1 and β3 integrins are involved.
Methods: The impact of isolated or combined platelet deficiency in β1 and β3 integrins on inflammation-associated hemostasis was investigated in 3 models of acute inflammation: immune complex-based cutaneous reverse passive Arthus reaction, intranasal lipopolysaccharide-induced lung inflammation, and cerebral ischemia-reperfusion following transient (2-hour) occlusion of the transient middle cerebral artery.
Results: Mice with platelet-directed inactivation of Itgb1 (PF4Cre-β1-/-) displayed no bleeding in any of the inflammation models, while mice defective in platelet Itgb3 (PF4Cre-β3-/-) exhibited bleeding in all 3 models. Remarkably, the bleeding phenotype of PF4Cre-β3-/- mice was exacerbated in the reverse passive Arthus model by the concomitant deletion of β1 integrins, PF4Cre-β1-/-/β3-/- animals presenting increased bleeding. Intravital microscopy in reverse passive Arthus experiments highlighted a major defect in the adhesion of PF4Cre-β1-/-/β3-/- platelets to inflamed microvessels. Unlike PF4Cre-β1-/- and PF4Cre-β3-/- mice, PF4Cre-β1-/-/β3-/- animals developed early hemorrhagic transformation 6 hours after transient middle cerebral artery occlusion. PF4Cre-β1-/-/β3-/- mice displayed no more bleeding in lipopolysaccharide-induced lung inflammation than PF4Cre-β3-/- animals.
Conclusions: Altogether, these results show that the requirement for and degree of functional redundancy between platelet β1 and β3 integrins in inflammation-associated hemostasis vary with the inflammatory situation.
{"title":"Cooperation Between Platelet β1 and β3 Integrins in the Arrest of Bleeding Under Inflammatory Conditions in Mice.","authors":"Emily Janus-Bell, Nicolas Receveur, Luc Mercier, Clarisse Mouriaux, Stéphanie Magnenat, Jochen Reiser, François Lanza, Béatrice Hechler, Benoit Ho-Tin-Noé, Pierre H Mangin","doi":"10.1161/ATVBAHA.124.321104","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.321104","url":null,"abstract":"<p><strong>Background: </strong>Platelets prevent bleeding in a variety of inflammatory settings, the adhesion receptors and activation pathways involved being highly context-dependent and functionally redundant. In some situations, platelets recruited to inflammatory sites act independently of aggregation. The mechanisms underlying stable platelet adhesion in inflamed microvessels remain incompletely understood, in particular, whether and if so, how β1 and β3 integrins are involved.</p><p><strong>Methods: </strong>The impact of isolated or combined platelet deficiency in β1 and β3 integrins on inflammation-associated hemostasis was investigated in 3 models of acute inflammation: immune complex-based cutaneous reverse passive Arthus reaction, intranasal lipopolysaccharide-induced lung inflammation, and cerebral ischemia-reperfusion following transient (2-hour) occlusion of the transient middle cerebral artery.</p><p><strong>Results: </strong>Mice with platelet-directed inactivation of <i>Itgb1</i> (PF4Cre-β1<sup>-/-</sup>) displayed no bleeding in any of the inflammation models, while mice defective in platelet <i>Itgb3</i> (PF4Cre-β3<sup>-/-</sup>) exhibited bleeding in all 3 models. Remarkably, the bleeding phenotype of PF4Cre-β3<sup>-/</sup><sup>-</sup> mice was exacerbated in the reverse passive Arthus model by the concomitant deletion of β1 integrins, PF4Cre-β1<sup>-/-</sup>/β3<sup>-/-</sup> animals presenting increased bleeding. Intravital microscopy in reverse passive Arthus experiments highlighted a major defect in the adhesion of PF4Cre-β1<sup>-/-</sup>/β3<sup>-/-</sup> platelets to inflamed microvessels. Unlike PF4Cre-β1<sup>-/-</sup> and PF4Cre-β3<sup>-/-</sup> mice, PF4Cre-β1<sup>-/-</sup>/β3<sup>-/-</sup> animals developed early hemorrhagic transformation 6 hours after transient middle cerebral artery occlusion. PF4Cre-β1<sup>-/-</sup>/β3<sup>-/-</sup> mice displayed no more bleeding in lipopolysaccharide-induced lung inflammation than PF4Cre-β3<sup>-/-</sup> animals.</p><p><strong>Conclusions: </strong>Altogether, these results show that the requirement for and degree of functional redundancy between platelet β1 and β3 integrins in inflammation-associated hemostasis vary with the inflammatory situation.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981504","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}
Pub Date : 2024-08-15DOI: 10.1161/ATVBAHA.124.320886
Anna Krzyżewska, Kondababu Kurakula
Pulmonary hypertension is a rare, incurable, and progressive disease. Although there is increasing evidence that immune disorders, particularly those associated with connective tissue diseases, are a strong predisposing factor in the development of pulmonary arterial hypertension (PAH), there is currently a lack of knowledge about the detailed molecular mechanisms responsible for this phenomenon. Exploring this topic is crucial because patients with an immune disorder combined with PAH have a worse prognosis and higher mortality compared with patients with other PAH subtypes. Moreover, data recorded worldwide show that the prevalence of PAH in women is 2× to even 4× higher than in men, and the ratio of PAH associated with autoimmune diseases is even higher (9:1). Sexual dimorphism in the pathogenesis of cardiovascular disease was explained for many years by the action of female sex hormones. However, there are increasing reports of interactions between sex hormones and sex chromosomes, and differences in the pathogenesis of cardiovascular disease may be controlled not only by sex hormones but also by sex chromosome pathways that are not dependent on the gonads. This review discusses the role of estrogen and genetic factors including the role of genes located on the X chromosome, as well as the potential protective role of the Y chromosome in sexual dimorphism, which is prominent in the occurrence of PAH associated with autoimmune diseases. Moreover, an overview of animal models that could potentially play a role in further investigating the aforementioned link was also reviewed.
肺动脉高压是一种罕见的、无法治愈的渐进性疾病。尽管越来越多的证据表明,免疫紊乱,尤其是与结缔组织疾病相关的免疫紊乱,是肺动脉高压(PAH)发病的一个强有力的易感因素,但目前对造成这一现象的详细分子机制还缺乏了解。探讨这一课题至关重要,因为与其他 PAH 亚型患者相比,免疫紊乱合并 PAH 的患者预后更差,死亡率更高。此外,全球记录的数据显示,女性 PAH 患病率是男性的 2 倍甚至 4 倍,而 PAH 与自身免疫性疾病相关的比例更高(9:1)。多年来,心血管疾病发病机制中的性别双态性一直被解释为女性性激素的作用。然而,关于性激素与性染色体之间相互作用的报道越来越多,心血管疾病发病机制的差异可能不仅受性激素的控制,还受不依赖于性腺的性染色体途径的控制。本综述讨论了雌激素和遗传因素的作用,包括位于 X 染色体上的基因的作用,以及 Y 染色体在性双态性中的潜在保护作用,这在与自身免疫性疾病相关的 PAH 的发生中尤为突出。此外,还综述了有可能在进一步研究上述联系方面发挥作用的动物模型。
{"title":"Sex Dimorphism in Pulmonary Arterial Hypertension Associated With Autoimmune Diseases.","authors":"Anna Krzyżewska, Kondababu Kurakula","doi":"10.1161/ATVBAHA.124.320886","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.320886","url":null,"abstract":"<p><p>Pulmonary hypertension is a rare, incurable, and progressive disease. Although there is increasing evidence that immune disorders, particularly those associated with connective tissue diseases, are a strong predisposing factor in the development of pulmonary arterial hypertension (PAH), there is currently a lack of knowledge about the detailed molecular mechanisms responsible for this phenomenon. Exploring this topic is crucial because patients with an immune disorder combined with PAH have a worse prognosis and higher mortality compared with patients with other PAH subtypes. Moreover, data recorded worldwide show that the prevalence of PAH in women is 2× to even 4× higher than in men, and the ratio of PAH associated with autoimmune diseases is even higher (9:1). Sexual dimorphism in the pathogenesis of cardiovascular disease was explained for many years by the action of female sex hormones. However, there are increasing reports of interactions between sex hormones and sex chromosomes, and differences in the pathogenesis of cardiovascular disease may be controlled not only by sex hormones but also by sex chromosome pathways that are not dependent on the gonads. This review discusses the role of estrogen and genetic factors including the role of genes located on the X chromosome, as well as the potential protective role of the Y chromosome in sexual dimorphism, which is prominent in the occurrence of PAH associated with autoimmune diseases. Moreover, an overview of animal models that could potentially play a role in further investigating the aforementioned link was also reviewed.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981507","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}