Wenqi Ma, Kangni Jia, Haomai Cheng, Hong Xu, Zhigang Li, Hang Zhang, Hongyang Xie, Lingfang Zhuang, Ziyang Wang, Yuke Cui, Hang Sun, Lei Yi, Zhiyong Chen, Shengzhong Duan, Motoaki Sano, Keiichi Fukuda, Lin Lu, Fei Gao, Ruiyan Zhang, Xiaoxiang Yan
BACKGROUND: Medial arterial calcification is a chronic systemic vascular disorder distinct from atherosclerosis and is commonly observed in patients with chronic kidney disease, diabetes, and aging individuals. We previously showed that NR4A3 (nuclear receptor subfamily 4 group A member 3), an orphan nuclear receptor, is a key regulator in apo (apolipoprotein) A-IV-induced atherosclerosis progression; however, its role in vascular calcification is poorly understood. METHODS: We generated NR4A3-/- mice and 2 different types of medial arterial calcification models to investigate the biological roles of NR4A3 in vascular calcification...
April 17, 2024: Circulation Research
Néstor de la Visitación, Wei Chen, Jaya Krishnan, Justin P Van Beusecum, Venkataraman Amarnath, Elizabeth M Hennen, Shilin Zhao, Mohammad Saleem, Mingfang Ao, Sergey I Dikalov, Anna E Dikalova, David G Harrison, David M Patrick
BACKGROUND: Hypertension is characterized by CD8+ T cell activation and infiltration into peripheral tissues. CD8+ T cell activation requires proteasomal processing of antigenic proteins. It has become clear that isoLG (isolevuglandin)-adduced peptides are antigenic in hypertension; however, IsoLGs inhibit the constitutive proteasome. We hypothesized that immunoproteasomal processing of isoLG-adducts is essential for CD8+ T cell activation and inflammation in hypertension. METHODS: IsoLG adduct processing was studied in murine dendritic cells (DCs), endothelial cells (ECs), and B8 fibroblasts...
April 16, 2024: Circulation Research
AnnJosette Ramirez, Christina A Vyzas, Huaning Zhao, Kevin Eng, Karl Degenhardt, Sophie Astrof
BACKGROUND: The resiliency of embryonic development to genetic and environmental perturbations has been long appreciated; however, little is known about the mechanisms underlying the robustness of developmental processes. Aberrations resulting in neonatal lethality are exemplified by congenital heart disease arising from defective morphogenesis of pharyngeal arch arteries (PAAs) and their derivatives. OBJECTIVE: To uncover mechanisms underlying the robustness of PAA morphogenesis...
April 15, 2024: Circulation Research
Arielys Mendoza, Pooja Patel, Dexter Robichaux, Daniel Ramirez, Jason Karch
BACKGROUND: During myocardial ischemia/reperfusion (I/R) injury, high levels of matrix Ca2+ and reactive oxygen species (ROS) induce the opening of the mitochondrial permeability transition pore (mPTP), which causes mitochondrial dysfunction and ultimately necrotic death. However, the mechanisms of how these triggers individually or cooperatively open the pore have yet to be determined. METHODS: Here, we use a combination of isolated mitochondrial assays and in vivo I/R surgery in mice...
April 15, 2024: Circulation Research
Tianpeng Wang, Jingchen Shao, Shamit Kumar, Mohammad Wessam Alnouri, Jorge Carvalho, Stefan Günther, Cornelius Krasel, Kate T Murphy, Moritz Bünemann, Stefan Offermanns, Nina Wettschureck
BACKGROUND: GPCRs (G-protein-coupled receptors) play a central role in the regulation of smooth muscle cell (SMC) contractility, but the function of SMC-expressed orphan GPCR class C group 5 member C (GPRC5C) is unclear. OBJECTIVE: The aim of this project is to define the role of GPRC5C in SMC in vitro and in vivo. METHODS AND RESULTS: We studied the role of GPRC5C in the regulation of SMC contractility and differentiation in human and murine SMC in vitro, as well as in tamoxifen-inducible, SMC-specific GPRC5C knockout mice under basal conditions and in vascular disease in vivo...
April 10, 2024: Circulation Research
Konstantinos Zifkos, Magdalena L Bochenek, Rajinikanth Gogiraju, Stephane Robert, Denise Pedrosa, Klytaimnistra Kiouptsi, Kateryna Moiko, Mathias Wagner, Felix Mahfoud, Philippe Poncelet, Thomas Münzel, Wolfram Ruf, Christoph Reinhardt, Laurence Panicot-Dubois, Christophe Dubois, Katrin Schäfer
BACKGROUND: Endothelial activation promotes the release of procoagulant extracellular vesicles and inflammatory mediators from specialized storage granules. Endothelial membrane exocytosis is controlled by phosphorylation. We hypothesized that the absence of PTP1B (protein tyrosine phosphatase 1B) in endothelial cells promotes venous thromboinflammation by triggering endothelial membrane fusion and exocytosis. METHODS: Mice with inducible endothelial deletion of PTP1B (End...
April 2, 2024: Circulation Research
Anita Tamiato, Lukas S Tombor, Ariane Fischer, Marion Muhly-Reinholz, Leah Rebecca Vanicek, Büşra Nur Toğru, Jessica Neitz, Simone Franziska Glaser, Maximilian Merten, David Rodriguez Morales, Jeonghyeon Kwon, Stephan Klatt, Bianca Schumacher, Stefan Günther, Wesley T Abplanalp, David John, Ingrid Fleming, Nina Wettschureck, Stefanie Dimmeler, Guillermo Luxán
BACKGROUND: Pericytes are capillary-associated mural cells involved in the maintenance and stability of the vascular network. Although aging is one of the main risk factors for cardiovascular disease, the consequences of aging on cardiac pericytes are unknown. METHODS: In this study, we have combined single-nucleus RNA sequencing and histological analysis to determine the effects of aging on cardiac pericytes. Furthermore, we have conducted in vivo and in vitro analysis of RGS5 (regulator of G-protein signaling 5) loss of function and finally have performed pericytes-fibroblasts coculture studies to understand the effect of RGS5 deletion in pericytes on the neighboring fibroblasts...
April 2, 2024: Circulation Research
Junxiong Chen, Yingjun Ding, Chao Jiang, Rongmei Qu, Jonathan D Wren, Constantin Georgescu, Xuejun Wang, Darlene N Reuter, Beibei Liu, Cory B Giles, Christoph H Mayr, Herbert B Schiller, Jingxing Dai, Christopher S Stipp, Bharathiraja Subramaniyan, Jie Wang, Houjuan Zuo, Chao Huang, Kar-Ming Fung, Heather C Rice, Arnoud Sonnenberg, David Wu, Matthew S Walters, You-Yang Zhao, Tomoharu Kanie, Franklin A Hays, James F Papin, Dao Wen Wang, Xin A Zhang
BACKGROUND: Tetraspanin CD151 is highly expressed in endothelia and reinforces cell adhesion, but its role in vascular inflammation remains largely unknown. METHODS: In vitro molecular and cellular biological analyses on genetically modified endothelial cells, in vivo vascular biological analyses on genetically engineered mouse models, and in silico systems biology and bioinformatics analyses on CD151-related events. RESULTS: Endothelial ablation of Cd151 leads to pulmonary and cardiac inflammation, severe sepsis, and perilous COVID-19, and endothelial CD151 becomes downregulated in inflammation...
April 1, 2024: Circulation Research
Roman Tikhomirov, Robert H Oakley, Cali Anderson, Yirong Xiang, Sami Al Othman, Matthew Smith, Sana Yaar, Eleonora Torre, Jianying Li, Leslie R Wilson, David R Goulding, Ian Donaldson, Erika Harno, Luca Soattin, Holly A Shiels, Gwilym M Morris, Henggui Zhang, Mark R Boyett, John A Cidlowski, Pietro Mesirca, Matteo E Mangoni, Alicia D'Souza
RATIONALE: Ventricular arrhythmias (VAs) demonstrate a prominent day-night rhythm, commonly presenting in the early morning. Transcriptional rhythms in cardiac ion channels accompany this phenomenon, but their role in the morning vulnerability to VAs and the underlying mechanisms are not understood. OBJECTIVE: The objectives are to investigate the recruitment of transcription factors to time-of-day differentially accessible chromatin that underpins day-night ion channel rhythms and to assess the significance of this for the heart's day-night rhythm in VA susceptibility...
March 27, 2024: Circulation Research
Kajsa Arkelius, Trevor S Wendt, Henrik Andersson, Anaële Arnou, Michael Gottschalk, Rayna J Gonzales, Saema Ansar
BACKGROUND: Acute ischemic stroke triggers endothelial activation that disrupts vascular integrity and increases hemorrhagic transformation leading to worsened stroke outcomes. rt-PA (recombinant tissue-type plasminogen activator) is an effective treatment; however, its use is limited due to a restricted time window and hemorrhagic transformation risk, which in part may involve activation of MMPs (matrix metalloproteinases) mediated through LOX-1 (lectin-like oxLDL [oxidized low-density lipoprotein] receptor 1)...
March 19, 2024: Circulation Research
Francisco M Cruz, Álvaro Macías, Ana I Moreno-Manuel, Lilian K Gutiérrez, María Linarejos Vera-Pedrosa, Isabel Martínez-Carrascoso, Patricia Sánchez Pérez, Juan Manuel Ruiz Robles, Francisco J Bermúdez-Jiménez, Aitor Díaz-Agustín, Fernando Martínez de Benito, Salvador Arias-Santiago, Aitana Braza-Boils, Mercedes Martín-Martínez, Marta Gutierrez-Rodríguez, Juan A Bernal, Esther Zorio, Juan Jiménez-Jaimez, José Jalife
BACKGROUND: Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K+ channel Kir2.1. The extracellular Cys (cysteine)122 -to-Cys154 disulfide bond in the channel structure is crucial for proper folding but has not been associated with correct channel function at the membrane. We evaluated whether a human mutation at the Cys122 -to-Cys154 disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2...
March 18, 2024: Circulation Research
Anthony L Hessel, Michel N Kuehn, Nichlas M Engels, Devin L Nissen, Johanna K Freundt, Weikang Ma, Thomas C Irving, Wolfgang A Linke
No abstract text is available yet for this article.
March 14, 2024: Circulation Research
Qiankun Bao, Bangying Zhang, Lu Zhou, Qian Yang, Xiaofeng Mu, Xing Liu, Shiying Zhang, Meng Yuan, Yue Zhang, Jingjin Che, Wen Wei, Tong Liu, Guangping Li, Jinlong He
BACKGROUND: CNP (C-type natriuretic peptide), an endogenous short peptide in the natriuretic peptide family, has emerged as an important regulator to govern vascular homeostasis. However, its role in the development of atherosclerosis remains unclear. This study aimed to investigate the impact of CNP on the progression of atherosclerotic plaques and elucidate its underlying mechanisms. METHODS: Plasma CNP levels were measured in patients with acute coronary syndrome...
March 8, 2024: Circulation Research
Onorina Laura Manzo, Jasmine Nour, Linda Sasset, Alice Marino, Luisa Rubinelli, Sailesh Palikhe, Martina Smimmo, Yang Hu, Maria Rosaria Bucci, Alain Borczuk, Olivier Elemento, Julie K Freed, Giuseppe Danilo Norata, Annarita Di Lorenzo
BACKGROUND: Growing evidence correlated changes in bioactive sphingolipids, particularly S1P (sphingosine-1-phosphate) and ceramides, with coronary artery diseases. Furthermore, specific plasma ceramide species can predict major cardiovascular events. Dysfunction of the endothelium lining lesion-prone areas plays a pivotal role in atherosclerosis. Yet, how sphingolipid metabolism and signaling change and contribute to endothelial dysfunction and atherosclerosis remain poorly understood...
March 8, 2024: Circulation Research
Chen Li, Sara K Ture, Benjamin Nieves-Lopez, Sara K Blick-Nitko, Preeti Maurya, Alison C Livada, Tyler J Stahl, Minsoo Kim, Anthony P Pietropaoli, Craig N Morrell
BACKGROUND: While platelets have well-studied hemostatic functions, platelets are immune cells that circulate at the interface between the vascular wall and white blood cells. The physiological implications of these constant transient interactions are poorly understood. Activated platelets induce and amplify immune responses, but platelets may also maintain immune homeostasis in healthy conditions, including maintaining vascular integrity and T helper cell differentiation, meaning that platelets are central to both immune responses and immune quiescence...
March 8, 2024: Circulation Research
Aleix Rius Rigau, Yi-Nan Li, Alexandru-Emil Matei, Andrea-Hermina Györfi, Peter-Martin Bruch, Sarah Koziel, Veda Devakumar, Armando Gabrielli, Alexander Kreuter, Jiucun Wang, Sascha Dietrich, Georg Schett, Jörg H W Distler, Minrui Liang
BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disease that can serve as a model to study vascular changes in response to inflammation, autoimmunity, and fibrotic remodeling. Although microvascular changes are the earliest histopathologic manifestation of SSc, the vascular pathophysiology remains poorly understood. OBJECTIVE: We applied spatial proteomic approaches to deconvolute the heterogeneity of vascular cells at the single-cell level in situ and characterize cellular alterations of the vascular niches of patients with SSc...
March 5, 2024: Circulation Research
Dan Zhao, Zeng-Kang Huang, Yu Liang, Zhi-Jun Li, Xue-Wei Zhang, Kun-Hang Li, Hao Wu, Xu-Dong Zhang, Chen-Sheng Li, Dong An, Xue Sun, Ming-Xin An, Jun-Xiu Shi, Yi-Jun Bao, Li Tian, Di-Fei Wang, An-Hua Wu, Yu-Hua Chen, Wei-Dong Zhao
BACKGROUND: Microvascular complications are the major outcome of type 2 diabetes progression, and the underlying mechanism remains to be determined. METHODS: High-throughput RNA sequencing was performed using human monocyte samples from controls and diabetes. The transgenic mice expressing human CTSD (cathepsin D) in the monocytes was constructed using CD68 promoter. In vivo 2-photon imaging, behavioral tests, immunofluorescence, transmission electron microscopy, Western blot analysis, vascular leakage assay, and single-cell RNA sequencing were performed to clarify the phenotype and elucidate the molecular mechanism...
February 29, 2024: Circulation Research
Rachel L Padget, Michael J Zeitz, Grace A Blair, Xiaobo Wu, Michael D North, Mira T Tanenbaum, Kari E Stanley, Chelsea M Phillips, D Ryan King, Samy Lamouille, Robert G Gourdie, Gregory S Hoeker, Sharon A Swanger, Steven Poelzing, James W Smyth
BACKGROUND: Viral cardiac infection represents a significant clinical challenge encompassing several etiological agents, disease stages, complex presentation, and a resulting lack of mechanistic understanding. Myocarditis is a major cause of sudden cardiac death in young adults, where current knowledge in the field is dominated by later disease phases and pathological immune responses. However, little is known regarding how infection can acutely induce an arrhythmogenic substrate before significant immune responses...
February 28, 2024: Circulation Research
Xiaoxiao Liu, Baolei Li, Shuyun Wang, Erge Zhang, Megan Schultz, Marlin Touma, Andre Monteiro Da Rocha, Sylvia M Evans, Anne Eichmann, Todd Herron, Ruizhen Chen, Dingding Xiong, Alexander Jaworski, Stephen Weiss, Ming-Sing Si
Recently shown to regulate cardiac development, the secreted axon guidance molecule SLIT3 maintains its expression in the postnatal heart. Despite its known expression in the cardiovascular system after birth, SLIT3 's relevance to cardiovascular function in the postnatal state remains unknown. As such, the objectives of this study were to determine the postnatal myocardial sources of SLIT3 and to evaluate its functional role in regulating the cardiac response to pressure overload stress. We first found that SLIT3 transcription was increased in myocardial tissue obtained from patients with congenital heart defects that caused ventricular pressure overload...
February 27, 2024: Circulation Research
Xiaojing Sun, Hon-Chi Lee, Tong Lu
BACKGROUND: Vascular BK channel, composed of the large conductance Ca2+ -activated K+ channel αsubunit and the large conductance Ca2+ -activated K+ channel β1 subunits, is a key determinant of coronary vasorelaxation and its function is impaired in diabetic vessels. However, our knowledge of diabetic BK channel dysregulation is incomplete. The Sorbin homology and Sorbs2 (SH3 [Src homology 3] domain-containing protein 2) are ubiquitously expressed in arteries, but its role in vascular pathophysiology is unknown...
February 16, 2024: Circulation Research
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