Pub Date : 2024-07-05Epub Date: 2024-07-04DOI: 10.1161/RES.0000000000000681
{"title":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000681","DOIUrl":"https://doi.org/10.1161/RES.0000000000000681","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 2","pages":"262-264"},"PeriodicalIF":16.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533742","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 : 2024-07-05Epub Date: 2024-05-30DOI: 10.1161/CIRCRESAHA.123.323201
Wenhui Wei, Alan V Smrcka
Background: Chronically elevated neurohumoral drive, and particularly elevated adrenergic tone leading to β-adrenergic receptor (β-AR) overstimulation in cardiac myocytes, is a key mechanism involved in the progression of heart failure. β1-AR (β1-adrenergic receptor) and β2-ARs (β2-adrenergic receptor) are the 2 major subtypes of β-ARs present in the human heart; however, they elicit different or even opposite effects on cardiac function and hypertrophy. For example, chronic activation of β1-ARs drives detrimental cardiac remodeling while β2-AR signaling is protective. The underlying molecular mechanisms for cardiac protection through β2-ARs remain unclear.
Methods: β2-AR signaling mechanisms were studied in isolated neonatal rat ventricular myocytes and adult mouse ventricular myocytes using live cell imaging and Western blotting methods. Isolated myocytes and mice were used to examine the roles of β2-AR signaling mechanisms in the regulation of cardiac hypertrophy.
Results: Here, we show that β2-AR activation protects against hypertrophy through inhibition of phospholipaseCε signaling at the Golgi apparatus. The mechanism for β2-AR-mediated phospholipase C inhibition requires internalization of β2-AR, activation of Gi and Gβγ subunit signaling at endosome and ERK (extracellular regulated kinase) activation. This pathway inhibits both angiotensin II and Golgi-β1-AR-mediated stimulation of phosphoinositide hydrolysis at the Golgi apparatus ultimately resulting in decreased PKD (protein kinase D) and histone deacetylase 5 phosphorylation and protection against cardiac hypertrophy.
Conclusions: This reveals a mechanism for β2-AR antagonism of the phospholipase Cε pathway that may contribute to the known protective effects of β2-AR signaling on the development of heart failure.
背景:神经体液驱动力的长期升高,特别是肾上腺素能张力的升高导致心肌细胞中的β-肾上腺素能受体(β-AR)过度刺激,是心力衰竭进展的一个关键机制。β1-AR(β1-肾上腺素能受体)和β2-AR(β2-肾上腺素能受体)是人体心脏中存在的两种主要的β-AR亚型,但它们对心脏功能和肥大的影响不同,甚至相反。例如,β1-ARs 的慢性激活会导致有害的心脏重塑,而 β2-AR 信号转导则具有保护作用。方法:采用活细胞成像和 Western 印迹方法,在离体新生大鼠心室肌细胞和成年小鼠心室肌细胞中研究了β2-AR 信号传导机制。利用离体心肌细胞和小鼠研究了这些信号传导方法在调控心脏肥大中的作用:结果:我们在这里发现,β2-AR 激活通过抑制高尔基体上的磷脂酶 Cε 信号传导来防止肥大。β2-AR介导的磷脂酶C抑制机制需要β2-AR的内化、内质体中Gi和Gβγ亚基信号的激活以及ERK(细胞外调节激酶)的激活。这一途径可抑制血管紧张素 II 和高尔基体-β1-AR 介导的高尔基体磷酸肌醇水解刺激,最终导致 PKD(蛋白激酶 D)和组蛋白去乙酰化酶 5 磷酸化减少,并防止心脏肥大:结论:这揭示了β2-AR拮抗磷脂酶Cε通路的机制,该机制可能有助于已知的β2-AR信号对心衰发展的保护作用。
{"title":"Internalized β2-Adrenergic Receptors Oppose PLC-Dependent Hypertrophic Signaling.","authors":"Wenhui Wei, Alan V Smrcka","doi":"10.1161/CIRCRESAHA.123.323201","DOIUrl":"10.1161/CIRCRESAHA.123.323201","url":null,"abstract":"<p><strong>Background: </strong>Chronically elevated neurohumoral drive, and particularly elevated adrenergic tone leading to β-adrenergic receptor (β-AR) overstimulation in cardiac myocytes, is a key mechanism involved in the progression of heart failure. β1-AR (β1-adrenergic receptor) and β2-ARs (β2-adrenergic receptor) are the 2 major subtypes of β-ARs present in the human heart; however, they elicit different or even opposite effects on cardiac function and hypertrophy. For example, chronic activation of β1-ARs drives detrimental cardiac remodeling while β2-AR signaling is protective. The underlying molecular mechanisms for cardiac protection through β2-ARs remain unclear.</p><p><strong>Methods: </strong>β2-AR signaling mechanisms were studied in isolated neonatal rat ventricular myocytes and adult mouse ventricular myocytes using live cell imaging and Western blotting methods. Isolated myocytes and mice were used to examine the roles of β2-AR signaling mechanisms in the regulation of cardiac hypertrophy.</p><p><strong>Results: </strong>Here, we show that β2-AR activation protects against hypertrophy through inhibition of phospholipaseCε signaling at the Golgi apparatus. The mechanism for β2-AR-mediated phospholipase C inhibition requires internalization of β2-AR, activation of Gi and Gβγ subunit signaling at endosome and ERK (extracellular regulated kinase) activation. This pathway inhibits both angiotensin II and Golgi-β1-AR-mediated stimulation of phosphoinositide hydrolysis at the Golgi apparatus ultimately resulting in decreased PKD (protein kinase D) and histone deacetylase 5 phosphorylation and protection against cardiac hypertrophy.</p><p><strong>Conclusions: </strong>This reveals a mechanism for β2-AR antagonism of the phospholipase Cε pathway that may contribute to the known protective effects of β2-AR signaling on the development of heart failure.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e24-e38"},"PeriodicalIF":16.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11223973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175125","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 : 2024-07-05Epub Date: 2024-06-03DOI: 10.1161/CIRCRESAHA.123.323973
Thomas Gilliland, Jacqueline S Dron, Margaret Sunitha Selvaraj, Mark Trinder, Kaavya Paruchuri, Sarah M Urbut, Sara Haidermota, Rachel Bernardo, Md Mesbah Uddin, Michael C Honigberg, Gina M Peloso, Pradeep Natarajan
Background: Dyslipoproteinemia often involves simultaneous derangements of multiple lipid traits. We aimed to evaluate the phenotypic and genetic characteristics of combined lipid disturbances in a general population-based cohort.
Methods: Among UK Biobank participants without prevalent coronary artery disease, we used blood lipid and apolipoprotein B concentrations to ascribe individuals into 1 of 6 reproducible and mutually exclusive dyslipoproteinemia subtypes. Incident coronary artery disease risk was estimated for each subtype using Cox proportional hazards models. Phenome-wide analyses and genome-wide association studies were performed for each subtype, followed by in silico causal gene prioritization and heritability analyses. Additionally, the prevalence of disruptive variants in causal genes for Mendelian lipid disorders was assessed using whole-exome sequence data.
Results: Among 450 636 UK Biobank participants: 63 (0.01%) had chylomicronemia; 40 005 (8.9%) had hypercholesterolemia; 94 785 (21.0%) had combined hyperlipidemia; 13 998 (3.1%) had remnant hypercholesterolemia; 110 389 (24.5%) had hypertriglyceridemia; and 49 (0.01%) had mixed hypertriglyceridemia and hypercholesterolemia. Over a median (interquartile range) follow-up of 11.1 (10.4-11.8) years, incident coronary artery disease risk varied across subtypes, with combined hyperlipidemia exhibiting the largest hazard (hazard ratio, 1.92 [95% CI, 1.84-2.01]; P=2×10-16), even when accounting for non-HDL-C (hazard ratio, 1.45 [95% CI, 1.30-1.60]; P=2.6×10-12). Genome-wide association studies revealed 250 loci significantly associated with dyslipoproteinemia subtypes, of which 72 (28.8%) were not detected in prior single lipid trait genome-wide association studies. Mendelian lipid variant carriers were rare (2.0%) among individuals with dyslipoproteinemia, but polygenic heritability was high, ranging from 23% for remnant hypercholesterolemia to 54% for combined hyperlipidemia.
Conclusions: Simultaneous assessment of multiple lipid derangements revealed nuanced differences in coronary artery disease risk and genetic architectures across dyslipoproteinemia subtypes. These findings highlight the importance of looking beyond single lipid traits to better understand combined lipid and lipoprotein phenotypes and implications for disease risk.
{"title":"Genetic Architecture and Clinical Outcomes of Combined Lipid Disturbances.","authors":"Thomas Gilliland, Jacqueline S Dron, Margaret Sunitha Selvaraj, Mark Trinder, Kaavya Paruchuri, Sarah M Urbut, Sara Haidermota, Rachel Bernardo, Md Mesbah Uddin, Michael C Honigberg, Gina M Peloso, Pradeep Natarajan","doi":"10.1161/CIRCRESAHA.123.323973","DOIUrl":"10.1161/CIRCRESAHA.123.323973","url":null,"abstract":"<p><strong>Background: </strong>Dyslipoproteinemia often involves simultaneous derangements of multiple lipid traits. We aimed to evaluate the phenotypic and genetic characteristics of combined lipid disturbances in a general population-based cohort.</p><p><strong>Methods: </strong>Among UK Biobank participants without prevalent coronary artery disease, we used blood lipid and apolipoprotein B concentrations to ascribe individuals into 1 of 6 reproducible and mutually exclusive dyslipoproteinemia subtypes. Incident coronary artery disease risk was estimated for each subtype using Cox proportional hazards models. Phenome-wide analyses and genome-wide association studies were performed for each subtype, followed by in silico causal gene prioritization and heritability analyses. Additionally, the prevalence of disruptive variants in causal genes for Mendelian lipid disorders was assessed using whole-exome sequence data.</p><p><strong>Results: </strong>Among 450 636 UK Biobank participants: 63 (0.01%) had chylomicronemia; 40 005 (8.9%) had hypercholesterolemia; 94 785 (21.0%) had combined hyperlipidemia; 13 998 (3.1%) had remnant hypercholesterolemia; 110 389 (24.5%) had hypertriglyceridemia; and 49 (0.01%) had mixed hypertriglyceridemia and hypercholesterolemia. Over a median (interquartile range) follow-up of 11.1 (10.4-11.8) years, incident coronary artery disease risk varied across subtypes, with combined hyperlipidemia exhibiting the largest hazard (hazard ratio, 1.92 [95% CI, 1.84-2.01]; <i>P</i>=2×10<sup>-16</sup>), even when accounting for non-HDL-C (hazard ratio, 1.45 [95% CI, 1.30-1.60]; <i>P</i>=2.6×10<sup>-12</sup>). Genome-wide association studies revealed 250 loci significantly associated with dyslipoproteinemia subtypes, of which 72 (28.8%) were not detected in prior single lipid trait genome-wide association studies. Mendelian lipid variant carriers were rare (2.0%) among individuals with dyslipoproteinemia, but polygenic heritability was high, ranging from 23% for remnant hypercholesterolemia to 54% for combined hyperlipidemia.</p><p><strong>Conclusions: </strong>Simultaneous assessment of multiple lipid derangements revealed nuanced differences in coronary artery disease risk and genetic architectures across dyslipoproteinemia subtypes. These findings highlight the importance of looking beyond single lipid traits to better understand combined lipid and lipoprotein phenotypes and implications for disease risk.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"265-276"},"PeriodicalIF":16.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11223949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199505","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 : 2024-07-05Epub Date: 2024-07-04DOI: 10.1161/CIRCRESAHA.124.321567
David Wong, Julie Martinez, Pearl Quijada
The epicardium, previously viewed as a passive outer layer around the heart, is now recognized as an essential component in development, regeneration, and repair. In this review, we explore the cellular and molecular makeup of the epicardium, highlighting its roles in heart regeneration and repair in zebrafish and salamanders, as well as its activation in young and adult postnatal mammals. We also examine the latest technologies used to study the function of epicardial cells for therapeutic interventions. Analysis of highly regenerative animal models shows that the epicardium is essential in regulating cardiomyocyte proliferation, transient fibrosis, and neovascularization. However, despite the epicardium's unique cellular programs to resolve cardiac damage, it remains unclear how to replicate these processes in nonregenerative mammalian organisms. During myocardial infarction, epicardial cells secrete signaling factors that modulate fibrotic, vascular, and inflammatory remodeling, which differentially enhance or inhibit cardiac repair. Recent transcriptomic studies have validated the cellular and molecular heterogeneity of the epicardium across various species and developmental stages, shedding further light on its function under pathological conditions. These studies have also provided insights into the function of regulatory epicardial-derived signaling molecules in various diseases, which could lead to new therapies and advances in reparative cardiovascular medicine. Moreover, insights gained from investigating epicardial cell function have initiated the development of novel techniques, including using human pluripotent stem cells and cardiac organoids to model reparative processes within the cardiovascular system. This growing understanding of epicardial function holds the potential for developing innovative therapeutic strategies aimed at addressing developmental heart disorders, enhancing regenerative therapies, and mitigating cardiovascular disease progression.
{"title":"Exploring the Function of Epicardial Cells Beyond the Surface.","authors":"David Wong, Julie Martinez, Pearl Quijada","doi":"10.1161/CIRCRESAHA.124.321567","DOIUrl":"10.1161/CIRCRESAHA.124.321567","url":null,"abstract":"<p><p>The epicardium, previously viewed as a passive outer layer around the heart, is now recognized as an essential component in development, regeneration, and repair. In this review, we explore the cellular and molecular makeup of the epicardium, highlighting its roles in heart regeneration and repair in zebrafish and salamanders, as well as its activation in young and adult postnatal mammals. We also examine the latest technologies used to study the function of epicardial cells for therapeutic interventions. Analysis of highly regenerative animal models shows that the epicardium is essential in regulating cardiomyocyte proliferation, transient fibrosis, and neovascularization. However, despite the epicardium's unique cellular programs to resolve cardiac damage, it remains unclear how to replicate these processes in nonregenerative mammalian organisms. During myocardial infarction, epicardial cells secrete signaling factors that modulate fibrotic, vascular, and inflammatory remodeling, which differentially enhance or inhibit cardiac repair. Recent transcriptomic studies have validated the cellular and molecular heterogeneity of the epicardium across various species and developmental stages, shedding further light on its function under pathological conditions. These studies have also provided insights into the function of regulatory epicardial-derived signaling molecules in various diseases, which could lead to new therapies and advances in reparative cardiovascular medicine. Moreover, insights gained from investigating epicardial cell function have initiated the development of novel techniques, including using human pluripotent stem cells and cardiac organoids to model reparative processes within the cardiovascular system. This growing understanding of epicardial function holds the potential for developing innovative therapeutic strategies aimed at addressing developmental heart disorders, enhancing regenerative therapies, and mitigating cardiovascular disease progression.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 2","pages":"353-371"},"PeriodicalIF":16.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11225799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533741","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 : 2024-07-05Epub Date: 2024-07-04DOI: 10.1161/CIRCRESAHA.124.324954
Jesus D Melgarejo
{"title":"Phosphodiesterase Inhibitors in Cerebrovascular Perfusion and Pulsatility.","authors":"Jesus D Melgarejo","doi":"10.1161/CIRCRESAHA.124.324954","DOIUrl":"10.1161/CIRCRESAHA.124.324954","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 2","pages":"332-334"},"PeriodicalIF":16.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533744","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 : 2024-07-05Epub Date: 2024-07-04DOI: 10.1161/CIRCRESAHA.124.324792
Chang Jie Mick Lee, Roger S-Y Foo
{"title":"TRIM35: A Proposed Gateway to p53-Induced Heart Failure Pathogenesis.","authors":"Chang Jie Mick Lee, Roger S-Y Foo","doi":"10.1161/CIRCRESAHA.124.324792","DOIUrl":"10.1161/CIRCRESAHA.124.324792","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 2","pages":"314-316"},"PeriodicalIF":16.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533745","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 : 2024-06-21Epub Date: 2024-05-17DOI: 10.1161/CIRCRESAHA.124.324486
Jacob R Blaustein, Heewon Alexandra Moon, Clarine Long, Luke J Bonanni, Terry Gordon, Lorna E Thorpe, Jonathan D Newman, Sharine Wittkopp
{"title":"Residences in Historically Redlined Districts in New York City Area Have More Indoor Particulate Air Pollution Potentially Reducible by Portable Air Cleaners.","authors":"Jacob R Blaustein, Heewon Alexandra Moon, Clarine Long, Luke J Bonanni, Terry Gordon, Lorna E Thorpe, Jonathan D Newman, Sharine Wittkopp","doi":"10.1161/CIRCRESAHA.124.324486","DOIUrl":"10.1161/CIRCRESAHA.124.324486","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e1-e3"},"PeriodicalIF":16.5,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11232086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140956401","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 : 2024-06-21Epub Date: 2024-06-20DOI: 10.1161/CIRCRESAHA.124.324573
Monika M Gladka
{"title":"From Grafts to Genes: Shaping Heart Care With Next-Generation Therapies.","authors":"Monika M Gladka","doi":"10.1161/CIRCRESAHA.124.324573","DOIUrl":"10.1161/CIRCRESAHA.124.324573","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 1","pages":"135-137"},"PeriodicalIF":16.5,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141431567","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}
Background: Hypoxia and oxidative stress contribute to the development of pulmonary hypertension (PH). tRNA-derived fragments play important roles in RNA interference and cell proliferation, but their epitranscriptional roles in PH development have not been investigated. We aimed to gain insight into the mechanistic contribution of oxidative stress-induced 8-oxoguanine in pulmonary vascular remodeling.
Methods: Through small RNA modification array analysis and quantitative polymerase chain reaction, a significant upregulation of the 8-oxoguanine -modified tRF-1-AspGTC was found in the lung tissues and the serum of patients with PH.
Results: This modification occurs at the position 5 of the tRF-1-AspGTC (5o8G tRF). Inhibition of the 5o8G tRF reversed hypoxia-induced proliferation and apoptosis resistance in pulmonary artery smooth muscle cells. Further investigation unveiled that the 5o8G tRF retargeted mRNA of WNT5A (Wingless-type MMTV integration site family, member 5A) and CASP3 (Caspase3) and inhibited their expression. Ultimately, BMPR2 (Bone morphogenetic protein receptor 2) -reactive oxygen species/5o8G tRF/WNT5A signaling pathway exacerbated the progression of PH.
Conclusions: Our study highlights the role of site-specific 8-oxoguanine-modified tRF in promoting the development of PH. Our findings present a promising therapeutic avenue for managing PH and propose 5o8G tRF as a potential innovative marker for diagnosing this disease.
{"title":"o<sup>8</sup>G Site-Specifically Modified tRF-1-AspGTC: A Novel Therapeutic Target and Biomarker for Pulmonary Hypertension.","authors":"Junting Zhang, Yiying Li, Yuan Chen, Jianchao Zhang, Zihui Jia, Muhua He, Xueyi Liao, Siyu He, Jin-Song Bian, Xiao-Wei Nie","doi":"10.1161/CIRCRESAHA.124.324421","DOIUrl":"10.1161/CIRCRESAHA.124.324421","url":null,"abstract":"<p><strong>Background: </strong>Hypoxia and oxidative stress contribute to the development of pulmonary hypertension (PH). tRNA-derived fragments play important roles in RNA interference and cell proliferation, but their epitranscriptional roles in PH development have not been investigated. We aimed to gain insight into the mechanistic contribution of oxidative stress-induced 8-oxoguanine in pulmonary vascular remodeling.</p><p><strong>Methods: </strong>Through small RNA modification array analysis and quantitative polymerase chain reaction, a significant upregulation of the 8-oxoguanine -modified tRF-1-AspGTC was found in the lung tissues and the serum of patients with PH.</p><p><strong>Results: </strong>This modification occurs at the position 5 of the tRF-1-AspGTC (5o<sup>8</sup>G tRF). Inhibition of the 5o<sup>8</sup>G tRF reversed hypoxia-induced proliferation and apoptosis resistance in pulmonary artery smooth muscle cells. Further investigation unveiled that the 5o<sup>8</sup>G tRF retargeted mRNA of WNT5A (Wingless-type MMTV integration site family, member 5A) and CASP3 (Caspase3) and inhibited their expression. Ultimately, BMPR2 (Bone morphogenetic protein receptor 2) -reactive oxygen species/5o<sup>8</sup>G tRF/WNT5A signaling pathway exacerbated the progression of PH.</p><p><strong>Conclusions: </strong>Our study highlights the role of site-specific 8-oxoguanine-modified tRF in promoting the development of PH. Our findings present a promising therapeutic avenue for managing PH and propose 5o<sup>8</sup>G tRF as a potential innovative marker for diagnosing this disease.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"76-92"},"PeriodicalIF":16.5,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920668","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}