Anti-inflammatory and antiatherogenic role of BMP receptor II in endothelial cells.

Abstract

OBJECTIVE:

Atherosclerosis is an inflammatory disease with multiple underlying metabolic and physical risk factors. Bone morphogenic protein 4 (BMP4) expression is increased in endothelium in atherosclerosis-prone regions and is known to induce endothelial inflammation, endothelial dysfunction, and hypertension. BMP actions are mediated by 2 different types of BMP receptors (BMPRI and BMPRII). Here, we show a surprising finding that loss of BMPRII expression causes endothelial inflammation and atherosclerosis.

APPROACH AND RESULTS:

Using BMPRII siRNA and BMPRII(+/-) mice, we found that specific knockdown of BMPRII, but not other BMP receptors (Alk1, Alk2, Alk3, Alk6, ActRIIa, and ActRIIb), induced endothelial inflammation in a ligand-independent manner by mechanisms mediated by reactive oxygen species, nuclear factor-KappaB, and reduced nicotinamide adenine dinucleotide phosphate oxidases. Further, BMPRII(+/-)ApoE(-/-) mice developed accelerated atherosclerosis compared with BMPRII(+/+)ApoE(-/-) mice. Interestingly, we found that multiple proatherogenic stimuli, such as hypercholesterolemia, disturbed flow, prohypertensive angiotensin II, and the proinflammatory cytokine (tumor necrosis factor-α), downregulated BMPRII expression in endothelium, whereas antiatherogenic stimuli, such as stable flow and statin treatment, upregulated its expression in vivo and in vitro. Moreover, BMPRII expression was significantly diminished in human coronary advanced atherosclerotic lesions. Also, we were able to rescue the endothelial inflammation induced by BMPRII knockdown by overexpressing the BMPRII wild type, but not by the BMPRII short form lacking the carboxyl-terminal tail region.

CONCLUSIONS:

These results suggest that BMPRII is a critical, anti-inflammatory, and antiatherogenic protein that is commonly targeted by multiple pro- and antiatherogenic factors. BMPRII may be used as a novel diagnostic and therapeutic target in atherosclerosis.

• Authors: Chan Woo Kim, Hannah Song, Sandeep Kumar, Douglas Nam, Hyuk Sang Kwon, Kyung Hwa Chang, Dong Ju Son, Dong-Won Kang, Seth A Brodie, Daiana Weiss, J David Vega, Noah Alberts-Grill, Kathy Griendling, W Robert Taylor, Hanjoong Jo
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 33 Issue 6 Pg. 1350-9 (Jun 2013) ISSN: 1524-4636 [Electronic] United States
• PMID: 23559633 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• NF-kappa B
• RNA, Small Interfering
• Reactive Oxygen Species
• Bone Morphogenetic Protein Receptors

Topics

• Animals
• Apolipoproteins E (deficiency)
• Atherosclerosis (genetics, metabolism)
• Bone Morphogenetic Protein Receptors (genetics, metabolism)
• Cells, Cultured
• Endothelial Cells (metabolism)
• Gene Expression Regulation
• Humans
• Mice
• Mice, Inbred Strains
• Models, Animal
• NF-kappa B (genetics, metabolism)
• RNA, Small Interfering (metabolism)
• Reactive Oxygen Species (metabolism)
• Reference Values
• Signal Transduction