Abstract 16568: Bmp Receptor II Reduction Causes Endothelial Inflammation in vitro and Increases Atherosclerosis in Apoe Knockout Mice
Atherosclerosis is an inflammatory disease, occurring preferentially in arterial regions exposed to disturbed flow. We have shown that in the endothelial cells (ECs), bone morphogenic protein-4 (BMP4) is produced in response to disturbed flow and acts as pro-inflammatory cytokine and its chronic infusion induces endothelial dysfunction and systemic hypertension in mice. Inhibition of BMP by matrix Gla protein (MGP) overexpression inhibits atherosclerosis further substantiates the role of BMP4 as pro-inflammatory and pro-atherogenic factor. However, which BMP receptors mediate the BMP4 action in endothelium is not clear. To test the functional importance of BMP receptor II (BMPRII), ECs were treated with BMPRII siRNA which resulted in blocked the BMP4 response_smad1/5/8 phosphorylation. Unexpectedly, BMPRII knockdown increased the ICAM-1 and VCAM-1 expression and monocyte adhesion in BMP4-independent manner. Interestingly, the siRNAs targeting other BMP receptors -ALK2, ALK3, Alk6, and ActRII- did not induce these inflammatory responses. Inhibitors of NADPH oxidases and NF-κB significantly attenuated the BMPRII- knockdown-induced inflammatory responses. Immunostaining for BMPRII showed intense staining of BMPRII in the “non-diseased” human coronary arteries; while it was virtually undetectable in the diseased arteries, suggesting a potential link between pro-atherosclerotic conditions and BMPRII levels. Furthermore, treating ECs with pro-inflammatory cytokines: TNFα and LPS decreased BMPRII expression by 2-fold. In contrast, cholesterol-lowering statins increased BMPRII by 4-fold. In vivo, in the disturbed flow-induced animal model of atherosclerosis (partial ligation and high-fat diet for 2 weeks), BMPRII reduction (using BMPRII+/-_ApoE-/- mice) developed significantly larger atherosclerotic lesion as determined by Oil-red-O staining in the left common carotid arteries (n=6, p<0.05) compared to BMPRII+/+_ApoE-/- control mice. In summary, we demonstrate for the first time that BMPRII can be modulated by pro- or anti-atherogenic conditions. BMPRII reduction in ECs induces inflammation in vitro and atherosclerosis in vivo. We propose that BMPRII plays an unexpected anti-inflammatory and anti-atherogenic role.
- © 2011 by American Heart Association, Inc.