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

BMPRII;Inflammation;Endothelial cells;Atherosclerosis

Song, Hannah ; Biomedical Engineering

University:Georgia Institute of Technology

Department:Biomedical Engineering

关键词: BMPRII;    Inflammation;    Endothelial cells;    Atherosclerosis;   

Others  :  https://smartech.gatech.edu/bitstream/1853/28258/1/Song_Hannah_200804_phd.pdf

美国|英语

来源: SMARTech Repository

【 摘 要 】

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.