Title:
Endothelial bone morphogenic protein 4 and bone morphogenic protein receptor II expression in inflammation and atherosclerosis

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dc.contributor.advisor Jo, Hanjoong
dc.contributor.author Song, Hannah en_US
dc.contributor.committeeMember Yoganathan, Ajit P.
dc.contributor.committeeMember Anew P. Kowalczyk
dc.contributor.committeeMember David G. Harrison
dc.contributor.committeeMember Kathy K. Griendling
dc.contributor.department Biomedical Engineering en_US
dc.date.accessioned 2009-06-08T19:33:45Z
dc.date.available 2009-06-08T19:33:45Z
dc.date.issued 2007-12-17 en_US
dc.description.abstract Atherosclerosis is an inflammatory disease, occurring preferentially in arterial regions with disturbed flow. We have shown that disturbed flow induces inflammation in endothelial cells (ECs) by producing bone morphogenic protein-4 (BMP4). Moreover, chronic BMP4 infusion induces endothelial dysfunction and systemic hypertension in mice. Here, we examined which BMP receptors (BMPR) mediate BMP4 action in ECs. Western blot, immunostaining and RT-PCR studies using human and bovine ECs, mouse aortas and human coronary arteries (HCA) showed that BMPRI (ALK2 and 6) and BMP-RII were expressed in ECs. As a functional test, ECs were treated with a BMPRII siRNA to knockdown expression. BMPRII knockdown blocked a well-known BMP4 response - smad1/5/8 phosphorylation, as expected. Unexpectedly, BMPRII knockdown itself significantly stimulated ICAM-1 and VCAM-1 expression and monocyte adhesion in a BMP4-independent manner. Inflammatory responses caused by BMPRII knockdown were blocked by inhibitors of NADPH oxidase and NFκ B. From these results, we hypothesized that BMP-RII knockdown in ECs would cause inflammation, which is a critical event in atherosclerosis initiation and progression. Genetic mutations of BMPRII have been linked to primary pulmonary hypertension. However, it is not known whether BMP-RII is regulated by atherosclerotic conditions and plays a role in non-pulmonary vessels causing inflammation and atherosclerosis. We examined BMPRII levels in HCA by immunostaining. While non-diseased arteries showed intense staining of BMPRII, the expression decreased as lesions became more advanced. BMPRII was virtually undetectable in the most advanced lesions. These findings suggested a potential link between pro-atherosclerotic conditions and BMP-RII levels. We tested this hypothesis by treating ECs with pro-inflammatory cytokines found in atheromas: TNFα decreased BMPRII by 2-fold. In contrast, statins increased BMPRII by 4-fold. In summary, we demonstrate for the first time that BMPRII can be down- or up-regulated by pro- or anti-atherogenic conditions, respectively, and it is dramatically decreased in HCA with advanced plaques. Moreover, BMPRII knockdown in ECs induces inflammation, a critical atherogenic step. We propose that focal inflammation initiated by disturbed flow, together with circulating pro-atherogenic risk factors, may lead to a vicious cycle of BMPRII down-regulation causing secondary inflammation and atheroma progression. en_US
dc.description.degree Ph.D. en_US
dc.identifier.uri http://hdl.handle.net/1853/28258
dc.publisher Georgia Institute of Technology en_US
dc.subject BMPRII en_US
dc.subject Inflammation en_US
dc.subject Endothelial cells en_US
dc.subject Atherosclerosis en_US
dc.subject.lcsh Atherosclerosis
dc.subject.lcsh Bone morphogenetic proteins
dc.subject.lcsh Endothelium
dc.subject.lcsh Inflammation
dc.subject.lcsh Atherosclerotic plaque
dc.title Endothelial bone morphogenic protein 4 and bone morphogenic protein receptor II expression in inflammation and atherosclerosis en_US
dc.type Text
dc.type.genre Dissertation
dspace.entity.type Publication
local.contributor.advisor Jo, Hanjoong
local.contributor.corporatename Wallace H. Coulter Department of Biomedical Engineering
local.contributor.corporatename College of Engineering
relation.isAdvisorOfPublication 7eb8fb49-de34-4fc6-aea8-80b31a2a2be8
relation.isOrgUnitOfPublication da59be3c-3d0a-41da-91b9-ebe2ecc83b66
relation.isOrgUnitOfPublication 7c022d60-21d5-497c-b552-95e489a06569
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