scholarly journals TGF-β Signaling-Related Genes and Thoracic Aortic Aneurysms and Dissections

2018 ◽  
Vol 19 (7) ◽  
pp. 2125 ◽  
Author(s):  
Norifumi Takeda ◽  
Hironori Hara ◽  
Takayuki Fujiwara ◽  
Tsubasa Kanaya ◽  
Sonoko Maemura ◽  
...  
Keyword(s):  
Connective Tissue ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Aortic Aneurysms ◽  
Loss Of Function ◽  
Angiotensin Ii Receptor ◽  
Thoracic Aortic Aneurysms ◽  
Structural Weakness ◽  
History Of

Transforming growth factor-β (TGF)-β signaling plays a crucial role in the development and maintenance of various organs, including the vasculature. Accordingly, the mutations in TGF-β signaling pathway-related genes cause heritable disorders of the connective tissue, such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and Shprintzen-Goldberg syndrome (SGS), and these syndromes may affect skeletal, ocular, pulmonary, and cardiovascular systems. Aortic root aneurysms are common problems that can result in aortic dissection or rupture, which is the leading cause of sudden death in the natural history of MFS and LDS, and recent improvements in surgical treatment have improved life expectancy. However, there is currently no genotype-specific medical treatment. Accumulating evidence suggest that not only structural weakness of connective tissue but also increased TGF-β signaling contributes to the complicated pathogenesis of aortic aneurysm formation, but a comprehensive understanding of governing molecular mechanisms remains lacking. Inhibition of angiotensin II receptor signaling and endothelial dysfunction have gained attention as a possible MFS treatment strategy, but interactions with TGF-β signaling remain elusive. Heterozygous loss-of-function mutations in TGF-β receptors 1 and 2 (TGFBR1 and TGFBR2) cause LDS, but TGF-β signaling is activated in the aorta (referred to as the TGF-β paradox) by mechanisms yet to be elucidated. In this review, we present and discuss the current understanding of molecular mechanisms responsible for aortopathies of MFS and related disorders.

scholarly journals Diverging Alternative Splicing Fingerprints in the Transforming Growth Factor-β Signaling Pathway Identified in Thoracic Aortic Aneurysms

2011 ◽  
Vol 17 (7-8) ◽  
pp. 665-675 ◽  
Author(s):  
Sanela Kurtovic ◽  
Valentina Paloschi ◽  
Lasse Folkersen ◽  
Johan Gottfries ◽  
Anders Franco-Cereceda ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Aortic Aneurysms ◽  
Thoracic Aortic Aneurysms

scholarly journals Mutations in Transforming Growth Factor-β Receptor Type II Cause Familial Thoracic Aortic Aneurysms and Dissections

Circulation ◽  
2005 ◽  
Vol 112 (4) ◽  
pp. 513-520 ◽  
Author(s):  
Hariyadarshi Pannu ◽  
Van Tran Fadulu ◽  
Jessica Chang ◽  
Andrea Lafont ◽  
Sumera N. Hasham ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Aortic Aneurysms ◽  
Receptor Type ◽  
Type Ii ◽  
Thoracic Aortic Aneurysms ◽  
Β Receptor

scholarly journals Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 183
Author(s):  
Tyler J. Creamer ◽  
Emily E. Bramel ◽  
Elena Gallo MacFarlane
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Aortic Aneurysms ◽  
Gene Products ◽  
Molecular Processes ◽  
Thoracic Aortic Aneurysms ◽  
Pathogenic Variants ◽  
The Matrix ◽  
Life Threatening ◽  
Causal Variants

Thoracic aortic aneurysms (TAA) are permanent and localized dilations of the aorta that predispose patients to a life-threatening risk of aortic dissection or rupture. The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required to maintain aortic homeostasis. Vascular smooth muscle cells (VSMCs) elaborate and remodel the extracellular matrix (ECM) in response to mechanical and biochemical cues from their environment. Causal variants for hereditary forms of aneurysm compromise the function of gene products involved in the transmission or interpretation of these signals, initiating processes that eventually lead to degeneration and mechanical failure of the vessel. These include mutations that interfere with transduction of stimuli from the matrix to the actin–myosin cytoskeleton through integrins, and those that impair signaling pathways activated by transforming growth factor-β (TGF-β). In this review, we summarize the features of the healthy aortic wall, the major pathways involved in the modulation of VSMC phenotypes, and the basic molecular functions impaired by TAA-associated mutations. We also discuss how the heterogeneity and balance of adaptive and maladaptive responses to the initial genetic insult might contribute to disease.

scholarly journals Transforming Growth Factor-β and the Renin-Angiotensin System in Syndromic Thoracic Aortic Aneurysms: Implications for Treatment

2020 ◽  
Author(s):  
Daan C.H. van Dorst ◽  
Nathalie P. de Wagenaar ◽  
Ingrid van der Pluijm ◽  
Jolien W. Roos-Hesselink ◽  
Jeroen Essers ◽  
...  
Keyword(s):  
Growth Factor ◽  
Medical Treatment ◽  
Transforming Growth Factor ◽  
Renin Angiotensin System ◽  
Transforming Growth Factor Β ◽  
Aortic Aneurysms ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Thoracic Aortic Aneurysms ◽  
Β Blockers

AbstractThoracic aortic aneurysms (TAAs) are permanent pathological dilatations of the thoracic aorta, which can lead to life-threatening complications, such as aortic dissection and rupture. TAAs frequently occur in a syndromic form in individuals with an underlying genetic predisposition, such as Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). Increasing evidence supports an important role for transforming growth factor-β (TGF-β) and the renin-angiotensin system (RAS) in TAA pathology. Eventually, most patients with syndromic TAAs require surgical intervention, as the ability of present medical treatment to attenuate aneurysm growth is limited. Therefore, more effective medical treatment options are urgently needed. Numerous clinical trials investigated the therapeutic potential of angiotensin receptor blockers (ARBs) and β-blockers in patients suffering from syndromic TAAs. This review highlights the contribution of TGF-β signaling, RAS, and impaired mechanosensing abilities of aortic VSMCs in TAA formation. Furthermore, it critically discusses the most recent clinical evidence regarding the possible therapeutic benefit of ARBs and β-blockers in syndromic TAA patients and provides future research perspectives and therapeutic implications.

scholarly journals Involvement of MAP3K7 in FMD2 and CSCF, delineation of genotype/phenotype correlations.

2021 ◽  
Author(s):  
Geeske van Woerden ◽  
Richelle Senden ◽  
Charlotte de Konink ◽  
Rossella Avagliano Trezza ◽  
anwar baban ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Connective Tissue ◽  
Noonan Syndrome ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Loss Of Function ◽  
Molecular Fingerprint ◽  
Clinical Phenotypes ◽  
Pathogenic Variants ◽  
Mitogen Activated Protein

Mitogen-Activated Protein 3 Kinase 7 (MAP3K7, MIM 602614) encodes the ubiquitously expressed transforming growth factor β (TGF-β)–activated kinase 1 (TAK1), which plays a crucial role in many cellular processes. Variants in the MAP3K7 gene have been linked to 2 distinct disorders: frontometaphyseal dysplasia type 2 (FMD2, MIM #617137) and cardiospondylocarpofacial syndrome (CSCF, MIM #157800). The fact that different variants can induce 2 distinct phenotypes suggests a phenotype/genotype correlation, but no side-by-side comparison has been done thus far to confirm this. Here we significantly expand the cohort and the description of clinical phenotypes for individuals with CSCF and FMD2 who carry variants in MAP3K7. We show that in contrast to FMD2-causing variants, CSCF-causing variants in MAP3K7 have a loss-of-function effect. Additionally, patients with pathogenic variants in MAP3K7 are at risk for cardiac disease, have symptoms associated with connective tissue disease and we show overlap in clinical phenotypes of CSCF with Noonan syndrome. Together, we provide evidence for a molecular fingerprint of FMD2- versus CSCF-causing MAP3K7 variants and conclude that variants in MAP3K7 should be considered in the differential diagnosis of patients with syndromic congenital cardiac defects and/or cardiomyopathy, syndromic connective tissue disorders and in the differential diagnosis of Noonan syndrome.

scholarly journals Expression and function of Smad7 in autoimmune and inflammatory diseases

2021 ◽  
Author(s):  
Yiping Hu ◽  
Juan He ◽  
Lianhua He ◽  
Bihua Xu ◽  
Qingwen Wang
Keyword(s):  
Posttranscriptional Regulation ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Kidney Diseases ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Signaling Mechanism ◽  
And Function

AbstractTransforming growth factor-β (TGF-β) plays a critical role in the pathological processes of various diseases. However, the signaling mechanism of TGF-β in the pathological response remains largely unclear. In this review, we discuss advances in research of Smad7, a member of the I-Smads family and a negative regulator of TGF-β signaling, and mainly review the expression and its function in diseases. Smad7 inhibits the activation of the NF-κB and TGF-β signaling pathways and plays a pivotal role in the prevention and treatment of various diseases. Specifically, Smad7 can not only attenuate growth inhibition, fibrosis, apoptosis, inflammation, and inflammatory T cell differentiation, but also promotes epithelial cells migration or disease development. In this review, we aim to summarize the various biological functions of Smad7 in autoimmune diseases, inflammatory diseases, cancers, and kidney diseases, focusing on the molecular mechanisms of the transcriptional and posttranscriptional regulation of Smad7.

scholarly journals The Potential Association between the Risk of Post-Surgical Adhesion and the Activated Local Angiotensin II Type 1 Receptors: Need for Novel Treatment Strategies

2021 ◽  
pp. 1-8
Author(s):  
Mahmood Tavakkoli ◽  
Saeed Aali ◽  
Borzoo Khaledifar ◽  
Gordon A. Ferns ◽  
Majid Khazaei ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Angiotensin Receptor Blockers ◽  
Surgical Techniques ◽  
Treatment Strategies ◽  
Transforming Growth Factor Β

<b><i>Background:</i></b> Post-surgical adhesion bands (PSABs) are a common complication after abdominal or pelvic surgeries for different reasons like cancer treatment. Despite improvements in surgical techniques and the administration of drugs or the use of physical barriers, there has only been limited improvement in the frequency of postoperative adhesions. Complications of PSAB are pain, infertility, intestinal obstruction, and increased mortality. The most important molecular mechanisms for the development of PSAB are inflammatory response, oxidative stress, and overexpression of pro-fibrotic molecules such as transforming growth factor β. However, questions remain about the pathogenesis of this problem, for example, the causes for individual differences or why certain tissue sites are more prone to post-surgical adhesions. <b><i>Summary:</i></b> Addressing the pathological causes of PSAB, the potential role of local angiotensin II/angiotensin II type 1 receptors (AngII/AT1R), may help to prevent this problem. <b><i>Key Message:</i></b> The objective of this article was to explore the role of the AngII/AT1R axis potential to induce PSAB and the therapeutic potential of angiotensin receptor blockers in the prevention and treatment of PSAB.

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