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Connective Tissue Disorders and Cardiovascular Complications: The Indomitable Role of Transforming Growth Factor-Beta Signaling

  • Jason B. Wheeler
  • John S. Ikonomidis
  • Jeffrey A. JonesEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 802)

Abstract

Marfan Syndrome (MFS) and Loeys-Dietz Syndrome (LDS) represent heritable connective tissue disorders that cosegregate with a similar pattern of cardiovascular defects (thoracic aortic aneurysm, mitral valve prolapse/regurgitation, and aortic root dilatation with regurgitation). This pattern of cardiovascular defects appears to be expressed along a spectrum of severity in many heritable connective tissue disorders and raises suspicion of a relationship between the normal development of connective tissues and the cardiovascular system. Given the evidence of increased transforming growth factor-beta (TGF-β) signaling in MFS and LDS, this signaling pathway may represent the common link in this relationship. To further explore this hypothetical link, this chapter will review the TGF-β signaling pathway, heritable connective tissue syndromes related to TGF-β receptor (TGFBR) mutations, and discuss the pathogenic contribution of TGF-β to these syndromes with a primary focus on the cardiovascular system.

Keywords

Shprintzen-Goldberg syndrome, hereditary hemorrhagic telangiectasia (HHT) Marfan syndrome (MFS) Loeys-Dietz syndrome (LDS) Primary pulmonary hypertension Fibrodysplasia ossificans progressiva (FOP) Familial thoracic aortic aneurysm and dissection syndrome (FTAAD) Smad TGF-β receptor Curacao diagnostic criteria 

Abbreviations

AAT

Aortic Aneurysm Thoracic

ACE

Angiotensin Converting Enzyme

ALK-1

Activin Receptor-like Kinase 1

ALK-3

Activin Receptor-like Kinase 3

ALK-5

Activin Receptor-like Kinase 5

AOS

Aneurysm-Osteoarthritis Syndrome

ATI

Angiotensin II Receptor Type I

ATII

Angiotensin II Receptor Type II

ATS

Arterial Tortuosity Syndrome

AVM

Arteriovenous Malformation

BAV

Bicuspid Aortic Valve

BMP

Bone Morphogenetic Protein

BMPR1A

Bone Morphogenetic Protein Receptor 1A

BMPR2

Bone Morphogenetic Protein Receptor 2

Co-Smad

Common Smad

CTGF

Connective Tissue Growth Factor

ECM

Extracellular Matrix

ERK1/2

Extracellular Signal-Regulated Kinase 1/2

EVAR

Endovascular Aortic Repair

FBN1

Fibrillin-1

FOP

Fibrodysplasia Ossificans Progressiva

FTAAD

Familial Thoracic Aortic Aneurysm and Dissection Syndrome

GI

Gastrointestinal

HHT1

Hereditary Hemorrhagic Telangiectasia, Type 1

HHT2

Hereditary Hemorrhagic Telangiectasia, Type 2

JNK

c-Jun N-terminal Kinase

LAP

Latent Associated Protein

LDS

Loeys-Dietz Syndrome

LLC

Large Latent Complex

LTBP

Latent Transforming Growth Factor-Beta Binding Protein

MAPK

Mitogen-Activated Protein Kinase

MFS

Marfan Syndrome

MMPs

Matrix Metalloproteinases

MVP

Mitral Valve Prolapse

OMIM

Online Mendelian Inheritance in Man

PAH

Pulmonary Artery Hypertension

PDA

Patent Ductus Arteriosus

PI3K

Phosphoinositide 3-Kinase

RA

Rheumatoid Arthritis

R-Smad

Receptor Smad

SARA

Smad Anchor for Receptor Activation

SGS

Shprintzen-Goldberg Syndrome

SLC2A10

Solute Carrier Family 2, Facilitated Glucose Transporter Member 10

SLE

Systemic Lupus Erythematosus

Smurf

Smad Ubiquitination Regulatory Factor

TAA

Thoracic Aortic Aneurysm

TAK1

Transforming Growth Factor-Beta Associated Kinase 1

TFs

Transcription Factors

TGF-β

Transforming Growth Factor-Beta

TGFBRI

Transforming Growth Factor-Beta Receptor, Type-I

TGFBRII

Transforming Growth Factor-Beta Receptor, Type-II

TIMPs

Tissue Inhibitors of Matrix Metalloproteinases

TRAF6

Tumor Necrosis Factor Receptor Associated Factor 6

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Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Jason B. Wheeler
    • 1
  • John S. Ikonomidis
    • 1
  • Jeffrey A. Jones
    • 1
    • 2
    Email author
  1. 1.Division of Cardiothoracic SurgeryMedical University of South CarolinaCharlestonUSA
  2. 2.Ralph H. Johnson Veterans Affairs Medical CenterCharlestonUSA

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