Match!

Lessons on the pathogenesis of aneurysm from heritable conditions

Published on May 1, 2011in Nature43.07
· DOI :10.1038/nature10145
Mark E. Lindsay20
Estimated H-index: 20
(Johns Hopkins University),
Harry C. Dietz90
Estimated H-index: 90
(Johns Hopkins University)
Abstract
Aortic aneurysm is common, accounting for 1–2% of all deaths in industrialized countries. Early theories of the causes of human aneurysm mostly focused on inherited or acquired defects in components of the extracellular matrix in the aorta. Although several mutations in the genes encoding extracellular matrix proteins have been recognized, more recent discoveries have shown important perturbations in cytokine signalling cascades and intracellular components of the smooth muscle contractile apparatus. The modelling of single-gene heritable aneurysm disorders in mice has shown unexpected involvement of the transforming growth factor-β cytokine pathway in aortic aneurysm, highlighting the potential for new therapeutic strategies.
  • References (101)
  • Citations (285)
📖 Papers frequently viewed together
14 Authors (Limin Zhu, ..., Xavier Jeunemaitre)
412 Citations
201141.06Science
16 Authors (Tammy M. Holm, ..., Harry C. Dietz)
308 Citations
539 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
References101
Newest
#1Tammy M. Holm (Johns Hopkins University)H-Index: 10
#2Jennifer Habashi (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 14
Last. Harry C. Dietz (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 90
view all 16 authors...
308 CitationsSource
#1Jennifer Habashi (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 14
#2Jefferson J. Doyle (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 9
Last. Harry C. Dietz (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 90
view all 10 authors...
Angiotensin II (AngII) mediates progression of aortic aneurysm, but the relative contribution of its type 1 (AT1) and type 2 (AT2) receptors remains unknown. We show that loss of AT2 expression accelerates the aberrant growth and rupture of the aorta in a mouse model of Marfan syndrome (MFS). The selective AT1 receptor blocker (ARB) losartan abrogated aneurysm progression in the mice; full protection required intact AT2 signaling. The angiotensin-converting enzyme inhibitor (ACEi) enalapril, whi...
306 CitationsSource
#1I. van de Laar (EUR: Erasmus University Rotterdam)H-Index: 3
#2Rogier A. Oldenburg (EUR: Erasmus University Rotterdam)H-Index: 23
Last. Aida M. Bertoli-Avella (EUR: Erasmus University Rotterdam)H-Index: 25
view all 26 authors...
Aida Bertoli-Avella and colleagues report the identification of SMAD3 mutations in individuals with a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. The mutations cause increased aortic expression of components of the TGF-β signaling pathway.
394 CitationsSource
#1Clifford E. Kashtan (UMN: University of Minnesota)H-Index: 42
#2Yoav Segal (UMN: University of Minnesota)H-Index: 22
Last. Terry Watnick (Johns Hopkins University)H-Index: 13
view all 6 authors...
Background. There have been isolated case reports of arterial disease in males with Alport syndrome (AS), a systemic disorder of Type IV collagen. In this paper, we describe five new cases of AS associated with significant aortic disease including dissection and aneurysm. Methods. We present brief clinical descriptions of five males with AS and aortic disease. We performed immunohistochemical analysis of the expression of the α5 chain of Type IV collagen in skin basement membranes from a previou...
32 CitationsSource
#1Pedro P. Rocha (Charité)H-Index: 14
#2Manuela Scholze (MPG: Max Planck Society)H-Index: 5
Last. Heinrich Schrewe (MPG: Max Planck Society)H-Index: 24
view all 4 authors...
The Mediator complex is commonly seen as a molecular bridge that connects DNA-bound transcription factors to the RNA polymerase II (Pol II) machinery. It is a large complex of 30 subunits that is present in all eukaryotes. The Med12 subunit has been implicated not only in the regulation of Pol II activity, but also in the binding of transcription factors to the bulk of the Mediator complex. We targeted Med12 in mouse embryonic stem cells to investigate the in vivo function of this subunit. We re...
100 CitationsSource
#1Jiumei CaoH-Index: 9
#2Li-MinGONGH-Index: 23
Last. Dianna M. MilewiczH-Index: 62
view all 10 authors...
Tuberous sclerosis complex (TSC) is a genetic disorder with pleiotropic manifestations caused by heterozygous mutations in either TSC1 or TSC2. One of the less investigated complications of TSC is the formation of aneurysms of the descending aorta, which are characterized on pathologic examination by smooth muscle cell (SMC) proliferation in the aortic media. SMCs were explanted from Tsc2+/− mice to investigate the pathogenesis of aortic aneurysms caused by TSC2 mutations. Tsc2+/− SMCs demonstra...
29 CitationsSource
#1Saptarsi M. Haldar (Case Western Reserve University)H-Index: 25
#2Yuan Lu (Case Western Reserve University)H-Index: 19
Last. Mukesh K. Jain (Case Western Reserve University)H-Index: 68
view all 16 authors...
Current therapies for diseases of heart muscle (cardiomyopathy) and aorta (aortopathy) include inhibitors of the renin-angiotensin system, β-adrenergic antagonists, and the statin class of cholesterol-lowering agents. These therapies have limited efficacy, as adverse cardiovascular events continue to occur with some frequency in patients taking these drugs. Although cardiomyopathy and aortopathy can coexist in a number of conditions (for example, Marfan’s syndrome, acromegaly, pregnancy, and agi...
73 CitationsSource
#1Dominique Langlois (University of Lyon)H-Index: 1
#2Mohammad Hneino (University of Lyon)H-Index: 1
Last. Jacques Yuan Li (University of Lyon)H-Index: 5
view all 7 authors...
To understand the role of TGF-β signaling in cardiovascular development, we generated mice with conditional deletion of the TGF-β type II receptor (TβRII) gene (Tgfbr2) in cells expressing the smooth muscle cell-specific protein SM22α. The SM22α promoter was active in tissues involved in cardiovascular development: vascular smooth muscle cells (VSMCs), epicardium and myocardium. All SM22-Cre+/−/Tgfbr2flox/flox embryos died during the last third of gestation. About half the mutant embryos exhibit...
51 CitationsSource
#1Jianbin HuangH-Index: 3
#2Elaine C. Davis (McGill University)H-Index: 44
Last. Hiromi YanagisawaH-Index: 36
view all 7 authors...
Rationale: Loss of fibulin-4 during embryogenesis results in perinatal lethality because of aneurysm rupture, and defective elastic fiber assembly has been proposed as an underlying cause for the aneurysm phenotype. However, aneurysms are never seen in mice deficient for elastin, or for fibulin-5, which absence also leads to compromised elastic fibers. Objective: We sought to determine the mechanism of aneurysm development in the absence of fibulin-4 and establish the role of fibulin-4 in aortic...
103 CitationsSource
TGF-β regulates many aspects of cellular performance relevant to tissue morphogenesis and homeostasis. Postnatal perturbation of TGF-β signaling contributes to the pathogenesis of many disease states, as recently exemplified through the study of Marfan syndrome (MFS), including aortic aneurysm and skeletal muscle myopathy. Heterogeneity in the regulation and consequences of TGF-β signaling, amplified in the context of disease, has engendered confusion and controversy regarding its utility as a t...
85 CitationsSource
Cited By285
Newest
#1Hisashi Sawada (UK: University of Kentucky)H-Index: 5
#2Hideyuki Higashi (Harvard University)
Last. Jessica J. Moorleghen (UK: University of Kentucky)H-Index: 17
view all 18 authors...
Background: The ascending aorta is a common location for thoracic aortopathies. Pathology predominates in the aortic media with disease severity being most apparent in outer laminar layers. In the ascending aorta, smooth muscle cells (SMCs) are derived from two embryonic origins: cardiac neural crest and second heart field (SHF). SMCs of these origins have distinct distributions, and the localization of SHF coincides with the regional specificity in some forms of thoracic aortopathies. However, ...
Source
#1Ashley Dawson (BCM: Baylor College of Medicine)H-Index: 1
#2Scott A. LeMaire (BCM: Baylor College of Medicine)H-Index: 50
1 CitationsSource
#2Yuan-Chih Su (PRC: China Medical University (PRC))
Last. Boon Lead Tee (UCSF: University of California, San Francisco)
view all 4 authors...
BackgroundAneurysm of proximal thoracic aorta (pTAA) is an often indolent, yet fatal disease. Although advancements in aneurysmal repair techniques have increased long-term survival rates, studies have proven that there are increases in perioperative risk for stroke incidence after pTAA surgery. Conversely, there is little evidence regarding the long-term stroke incidence in pTAA individuals, which strongly influences the morbidity, mortality, and usage of antithrombotic agents.MethodsUsing the ...
Source
#1Rajasekharreddy Pala (Chapman University)H-Index: 4
#2V. T. Anju (Pondicherry University)H-Index: 2
Last. Surya M. Nauli (Chapman University)H-Index: 24
view all 5 authors...
Cardiovascular diseases (CVDs) are one of the foremost causes of high morbidity and mortality globally. Preventive, diagnostic, and treatment measures available for CVDs are not very useful, which demands promising alternative methods. Nanoscience and nanotechnology open a new window in the area of CVDs with an opportunity to achieve effective treatment, better prognosis, and less adverse effects on non-target tissues. The application of nanoparticles and nanocarriers in the area of cardiology h...
Source
#1Xi Luo (HUST: Huazhong University of Science and Technology)
#2Shan Deng (HUST: Huazhong University of Science and Technology)
Last. Feng Zhu (HUST: Huazhong University of Science and Technology)H-Index: 33
view all 10 authors...
Loeys-Dietz syndrome (LDS) is a rare connective tissue genetic disorder that is caused by a pathogenic variant in genes of TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 or TGFB3. It is characterized by aggressive vascular pathology, aneurysms, arterial tortuosity, bifid uvula, hypertelorism and cleft palate. Here we present a 42-year-old female patient with LDS. The patient underwent rapidly progressing artery aneurysms and life-threatening aortic dissection. Spontaneous fracture of the first metatarsal b...
Source
#1James P. Pirruccello (Harvard University)H-Index: 12
#2Mark Chaffin (Broad Institute)H-Index: 17
Last. Lu-Chen Weng (Broad Institute)H-Index: 20
view all 26 authors...
The aorta is the largest blood vessel in the body, and enlargement or aneurysm of the aorta can predispose to dissection, an important cause of sudden death. While rare syndromes have been identified that predispose to aortic aneurysm, the common genetic basis for the size of the aorta remains largely unknown. By leveraging a deep learning architecture that was originally developed to recognize natural images, we trained a model to evaluate the dimensions of the ascending and descending thoracic...
Source
#1Jian Gong (UM: University of Michigan)H-Index: 1
#2Dong Zhou (UM: University of Michigan)
Last. Bo Yang (UM: University of Michigan)H-Index: 15
view all 7 authors...
Objective: SMAD3 pathogenic variants are associated with the development of thoracic aortic aneurysms. We sought to determine the role of SMAD3 in lineage-specific vascular smooth muscle cells (VSM...
Source
#1Javier Barallobre-Barreiro ('KCL': King's College London)H-Index: 16
#2Bart LoeysH-Index: 44
Last. Jason C. KovacicH-Index: 36
view all 6 authors...
Highlights •The middle arterial layer, the tunica media, is composed of circumferentially arranged layers of VSMCs that are separated by concentrically arranged elastic lamellae, a form of ECM. •Advances in genetics and proteomics approaches have facilitated dramatic progress in our understanding of the key role of the ECM in vascular health and disease. •The emerging discoveries regarding the role of ECM in the vasculature hold promise to be developed into novel clinical disease biomarkers and ...
Source
#1Joe Davis Velchev (University of Antwerp)
#2Aline Verstraeten (University of Antwerp)H-Index: 13
Last. Bart Loeys (Radboud University Nijmegen)H-Index: 44
view all 3 authors...
In the current issue of JEM, Kang et al. (https://doi.org/10.1084/jem.20191499) describe somatic mutations in the SMAD3 gene causing endosteal melorheostosis. Using osteoblast models, the identified mutations are demonstrated to exert a gain-of-function mechanism, augmenting transforming growth factor (TGF) beta signaling. These findings provide further insights into the genetic etiology of melorheostosis and consolidate the importance of the TGFbeta pathway in skeletal disorders.
Source
#1William C. Frankel (BCM: Baylor College of Medicine)H-Index: 3
#2Howard K. Song (OHSU: Oregon Health & Science University)H-Index: 25
view all 38 authors...
Abstract Background Although patients with various types of heritable aortopathy often require distal aortic repair, data are limited regarding the most extensive operations—open thoracoabdominal aortic aneurysm (TAAA) repairs. The objective of this multicenter registry study was to characterize TAAA repairs in a large cohort of patients with different heritable aortic diseases. Methods From the 3,699 patients enrolled at 8 participating centers in the Genetically Triggered Thoracic Aortic Aneur...
1 CitationsSource