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":null,"pages":null},"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":null,"pages":null},"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.123.323100
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
Background: 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.
Methods: We generated LDL receptor-deficient (Ldlr-/-) mouse models of T1D expressing human APOA1 (apolipoprotein A1). Ldlr-/-APOA1Tg mice exhibited the main human HDL subspecies. We also generated Ldlr-/-APOA1Tg 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.
Results: Diabetic Ldlr-/-APOA1Tg 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 Ldlr-/-APOA1Tg 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.
Conclusions: 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.
{"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><sup><i>-/-</i></sup>) mouse models of T1D expressing human APOA1 (apolipoprotein A1). <i>Ldlr</i><sup><i>-/-</i></sup><i>APOA1</i><sup><i>Tg</i></sup> mice exhibited the main human HDL subspecies. We also generated <i>Ldlr</i><sup><i>-/-</i></sup><i>APOA1</i><sup><i>Tg</i></sup> 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><sup><i>-/-</i></sup><i>APOA1</i><sup><i>Tg</i></sup> 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><sup><i>-/-</i></sup><i>APOA1</i><sup><i>Tg</i></sup> 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":null,"pages":null},"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}
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":null,"pages":null},"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.124.324792
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":null,"pages":null},"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 : 2024-07-05Epub 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":null,"pages":null},"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":null,"pages":null},"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 : 2024-06-21Epub 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":null,"pages":null},"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":null,"pages":null},"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}
Pub Date : 2024-06-21Epub Date: 2024-06-20DOI: 10.1161/CIRCRESAHA.124.323067
Samuel Liu, Preston J Anderson, Sudarshan Rajagopal, Robert J Lefkowitz, Howard A Rockman
GPCRs (G protein-coupled receptors), also known as 7 transmembrane domain receptors, are the largest receptor family in the human genome, with ≈800 members. GPCRs regulate nearly every aspect of human physiology and disease, thus serving as important drug targets in cardiovascular disease. Sharing a conserved structure comprised of 7 transmembrane α-helices, GPCRs couple to heterotrimeric G-proteins, GPCR kinases, and β-arrestins, promoting downstream signaling through second messengers and other intracellular signaling pathways. GPCR drug development has led to important cardiovascular therapies, such as antagonists of β-adrenergic and angiotensin II receptors for heart failure and hypertension, and agonists of the glucagon-like peptide-1 receptor for reducing adverse cardiovascular events and other emerging indications. There continues to be a major interest in GPCR drug development in cardiovascular and cardiometabolic disease, driven by advances in GPCR mechanistic studies and structure-based drug design. This review recounts the rich history of GPCR research, including the current state of clinically used GPCR drugs, and highlights newly discovered aspects of GPCR biology and promising directions for future investigation. As additional mechanisms for regulating GPCR signaling are uncovered, new strategies for targeting these ubiquitous receptors hold tremendous promise for the field of cardiovascular medicine.
{"title":"G Protein-Coupled Receptors: A Century of Research and Discovery.","authors":"Samuel Liu, Preston J Anderson, Sudarshan Rajagopal, Robert J Lefkowitz, Howard A Rockman","doi":"10.1161/CIRCRESAHA.124.323067","DOIUrl":"10.1161/CIRCRESAHA.124.323067","url":null,"abstract":"<p><p>GPCRs (G protein-coupled receptors), also known as 7 transmembrane domain receptors, are the largest receptor family in the human genome, with ≈800 members. GPCRs regulate nearly every aspect of human physiology and disease, thus serving as important drug targets in cardiovascular disease. Sharing a conserved structure comprised of 7 transmembrane α-helices, GPCRs couple to heterotrimeric G-proteins, GPCR kinases, and β-arrestins, promoting downstream signaling through second messengers and other intracellular signaling pathways. GPCR drug development has led to important cardiovascular therapies, such as antagonists of β-adrenergic and angiotensin II receptors for heart failure and hypertension, and agonists of the glucagon-like peptide-1 receptor for reducing adverse cardiovascular events and other emerging indications. There continues to be a major interest in GPCR drug development in cardiovascular and cardiometabolic disease, driven by advances in GPCR mechanistic studies and structure-based drug design. This review recounts the rich history of GPCR research, including the current state of clinically used GPCR drugs, and highlights newly discovered aspects of GPCR biology and promising directions for future investigation. As additional mechanisms for regulating GPCR signaling are uncovered, new strategies for targeting these ubiquitous receptors hold tremendous promise for the field of cardiovascular medicine.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11192237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141431568","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}