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MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II

Published on Apr 5, 2007in Human Molecular Genetics4.544
· DOI :10.1093/hmg/ddm201
Hariyadarshi Pannu18
Estimated H-index: 18
(University of Texas Health Science Center at Houston),
Van Tran-Fadulu12
Estimated H-index: 12
(University of Texas Health Science Center at Houston)
+ 12 AuthorsDianna M. Milewicz58
Estimated H-index: 58
(University of Texas Health Science Center at Houston)
Abstract
Non-syndromic thoracic aortic aneurysms and dissections (TAADs) are inherited in an autosomal dominant manner in 20% of cases. Familial TAAD is genetically heterogeneous and four loci have been mapped for this disease to date, including a locus at 16p for TAAD associated with patent ductus arteriosus (PDA). The defective gene at the 16p locus has recently been identified as the smooth muscle cell (SMC)-specific myosin heavy chain gene (MYH11). On sequencing MYH11 in 93 families with TAAD alone and three families with TAAD/PDA, we identified novel mutations in two families with TAAD/PDA, but none in families with TAAD alone. Histopathological analysis of aortic sections from two individuals with MYH11 mutations revealed SMC disarray and focal hyperplasia of SMCs in the aortic media. SMC hyperplasia leading to significant lumen narrowing in some of the vessels of the adventitia was also observed. Insulin-like growth factor-1 (IGF-1) was upregulated in mutant aortas as well as explanted SMCs, but no increase in transforming growth factor-b expression or downstream targets was observed. Enhanced expression of angiotensin-converting enzyme and markers of Angiotensin II (Ang II) vascular inflammation (macrophage inflammatory protein-1a and b) were also found. These data suggest that MYH11 mutations are likely to be specific to the phenotype of TAAD/PDA and result in a distinct aortic and occlusive vascular pathology potentially driven by IGF-1 and Ang II.
  • References (39)
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References39
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Abstract Angiotensin II (A-II), the major effector peptide of the renin angiotensin system potently accelerates progression of atherosclerosis. To investigate its effects on vascular inflammatory mechanisms, we elucidated vascular cytokine expression during early lesion development in A-II-infused atherosclerosis-prone LDLR −/− mice. Male LDLR −/− mice were placed on a "Western" high-fat diet for 4 weeks, followed by sham or A-II infusion for 7 weeks. Equal blood pressures and elevations in seru...
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Abstract Movement generated by the myosin motor is generally thought to be driven by distortion of an elastic element within the myosin molecule and subsequent release of the resulting strain. However, the location of this elastic element in myosin remains unclear. The myosin motor domain consists of four major subdomains connected by flexible joints. The SH1 helix is the joint that connects the converter subdomain to the other domains, and is thought to play an important role in arrangements of...
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Abstract Background The MYH11 gene codes for smooth muscle myosin heavy chain which has a critical function in maintaining vascular wall stability. Patients with this mutation most commonly have aortic and cardiac defects. Documented involvement of intracranial vessels is exceptional. Case Description and Results A 29-year-old female with a history of patent ductus arteriosus (PDA) and aortic dissection was found to have incidental bilateral stenosis of the terminal Internal Carotid Arteries (IC...
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