Is there a role for biomarkers in thoracic aortic aneurysm disease?

Balmforth, Damian; Harky, Amer; Adams, Benjamin; Yap, John; Shipolini, Alex; Roberts, Neil; Uppal, Rakesh; Bashir, Mohamad

doi:10.1007/s11748-017-0855-0

Cited by 23 publications

(21 citation statements)

References 57 publications

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“…Imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound are currently used for routine diagnosis and monitoring of aneurysms. However, these imaging tools cannot be used to accurately determine the pre-clinical status and predict the timing for dissection or rupture of aneurysms (reviewed in 53 ). It has been reported that aortic size does not always provide an accurate prediction for Type A or Type B aortic dissection 54–56 .…”

Section: Discussionmentioning

confidence: 99%

Role of Thrombospondin-1 in Mechanotransduction and Development of Thoracic Aortic Aneurysm in Mouse and Humans

Yamashiro¹,

Thang²,

Shin³

et al. 2018

Circulation Research

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Rationale Abnormal mechanosensing of smooth muscle cells (SMCs) resulting from the defective elastin-contractile units has been suggested to drive the formation of thoracic aortic aneurysms (TAAs); however, the precise molecular mechanism has not been elucidated. Objective The aim of this study was to identify the crucial mediator(s) involved in abnormal mechanosensing and propagation of biochemical signals during the aneurysm formation and to establish a basis for a novel therapeutic strategy. Methods and Results We used a mouse model of postnatal ascending aortic aneurysms (Fbln4SMKO; termed SMKO), in which deletion of Fbln4 leads to disruption of the elastin-contractile units caused by a loss of elastic lamina-SMC connections. In this mouse, upregulation of early growth response-1 (Egr1) and angiotensin converting enzyme leads to activation of angiotensin II signaling. Here we showed that the matricellular protein, thrombospondin-1 (Thbs1), was highly upregulated in SMKO ascending aortas and in human TAAs. Thbs1 was induced by mechanical stretch and Ang II in SMCs, for which Egr1 was required, and reduction of Fbln4 sensitized the cells to these stimuli and led to higher expression of Egr1 and Thbs1. Deletion of Thbs1 in SMKO mice prevented the aneurysm formation in approximately 80% of SMKO; Thbs1−/− (termed DKO) animals and suppressed slingshot-1 and cofilin de-phosphorylation, leading to the formation of normal actin filaments. Furthermore, elastic lamina-SMC connections were restored in DKO aortas and mechanical testing showed that structural and material properties of DKO aortas were markedly improved. Conclusions Thbs1 is a critical component of mechanotransduction as well as a modulator of elastic fiber organization. Maladaptive upregulation of Thbs1 results in disruption of elastin-contractile units and dysregulation of actin cytoskeletal remodeling, contributing to the development of ascending aortic aneurysms in vivo. Thbs1 may serve as a potential therapeutic target for treating TAAs.

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Section: Discussionmentioning

confidence: 99%

Role of Thrombospondin-1 in Mechanotransduction and Development of Thoracic Aortic Aneurysm in Mouse and Humans

Yamashiro¹,

Thang²,

Shin³

et al. 2018

Circulation Research

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“…We expected a molecular, whose concentration positive correlation with pathology, is convenient to be detected before rupture even obvious dilatation occurs in aortic (Balmforth et al, ). Unfortunately, the ideal biomarker still unknown.…”

Section: Discussionmentioning

confidence: 99%

Network‐based analysis reveals novel gene signatures in the peripheral blood of patients with sporadic nonsyndromic thoracic aortic aneurysm

Chen

Zhang

et al. 2019

Journal Cellular Physiology

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Thoracic aortic aneurysm (TAA), a serious cardiovascular disease that causes morbidity and mortality worldwide. At present, few biomarkers can accurately diagnose the appearance of TAA before dissection or rupture. Our research has the intention to investigate the developing applicable biomarkers for TAA promising clinically diagnostic biomarkers or probable regulatory targets for TAA. In our research, we built correlation networks utilizing the expression profile of peripheral blood mononuclear cell obtained from a public microarray data set (GSE9106). Furthermore, we chose the turquoise module, which has the strongest significance with TAA and was further analyzed. Fourteen genes that overlapped with differentially expressed proteins in the medial aortic layer were obtained. Subsequently, we verified the results applying quantitative polymerase chain reaction (Q-PCR) to our clinical specimen. In general, the Q-PCR results coincide with the majority of the expression profile. Fascinatingly, a notable change occurred in CLU, DES, MYH10, and FBLN5. In summary, using weighted gene coexpression analysis, our study indicates that CLU, DES, MYH10, and FBLN5 were identified and validated to be related to TAA and might be candidate biomarkers or therapeutic targets for TAA.

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“…Syndromic causes are the chief associated or causative pathologies behind the genetics of TAAD: all identified syndromes have effects on vessel integrity and the associated TAAD sudden deaths commonly plague these patients. Marfan syndrome (MFS, OMIM 154700) is an autosomal dominant connective tissue disorder that typically affects the skeletal and cardiovascular system ( 12 , 13 ). While MFS is associated with Marfan locus on chromosome 15, presentation remains highly variable ( 14 , 15 ).…”

Section: Genetics Of Aortic Aneurysm and Dissectionmentioning

confidence: 99%

The genetics and biomechanics of thoracic aortic diseases

Harky

Fan

2019

Vascular Biology

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Thoracic aortic aneurysms and aortic dissections (TAAD) are highly fatal emergencies within cardiothoracic surgery. With increasing age, thoracic aneurysms become more prevalent and pose an even greater threat when they develop into aortic dissections. Both diseases are multifactorial and are influenced by a multitude of physiological and biomechanical processes. Structural stability of aorta can be disrupted by genes, such as those for extracellular matrix and contractile protein, as well as telomere dysfunction, which leads to senescence of smooth muscle and endothelial cells. Biomechanical changes such as increased luminal pressure imposed by hypertension are also very prevalent and lead to structural instability. Furthermore, ageing is associated with a pro-inflammatory state that exacerbates degeneration of vessel wall, facilitating the development of both aortic aneurysms and aortic dissection. This literature review provides an overview of the aetiology and pathophysiology of both thoracic aneurysms and aortic dissections. With an improved understanding, new therapeutic targets may eventually be identified to facilitate treatment and prevention of these diseases.

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Is there a role for biomarkers in thoracic aortic aneurysm disease?

Cited by 23 publications

References 57 publications

Role of Thrombospondin-1 in Mechanotransduction and Development of Thoracic Aortic Aneurysm in Mouse and Humans

Role of Thrombospondin-1 in Mechanotransduction and Development of Thoracic Aortic Aneurysm in Mouse and Humans

Network‐based analysis reveals novel gene signatures in the peripheral blood of patients with sporadic nonsyndromic thoracic aortic aneurysm

The genetics and biomechanics of thoracic aortic diseases

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