MyD88 deficiency attenuates angiotensin II-induced abdominal aortic aneurysm formation independent of signaling through Toll-like receptors 2 and 4.

Abstract

OBJECTIVE:

The purpose of this study was to determine whether myeloid differentiation factor 88 (MyD88) and its related Toll-like receptors (TLRs) 2 and 4 contributed to the development of angiotensin II (AngII)-induced abdominal aortic aneurysms (AAAs) and atherosclerosis.

METHODS AND RESULTS:

AngII was infused into either apoE(-/-) or LDL receptor (LDLR)(-/-) male mice that were either MyD88(+/+) or (-/-). MyD88 deficiency profoundly reduced AngII-induced AAAs and atherosclerosis in both strains. To define whether deficiency of specific TLRs had similar effects, AngII was infused into LDLR(-/-) mice that were also deficient in either TLR2 or TLR4. TLR2 deficiency had no effect on AAA development but inhibited atherosclerosis. In contrast, TLR4 deficiency attenuated both AAAs and atherosclerosis. To resolve whether MyD88 and TLR4 exerted their effects through cells of hematopoietic lineage, LDLR(-/-) mice were lethally irradiated and repopulated with bone marrow-derived cells from either MyD88 or TLR4 strains. MyD88 deficiency in bone marrow-derived cells profoundly reduced both AngII-induced AAAs and atherosclerosis. However, TLR4 deficiency in bone marrow-derived cells had no effect on either pathology.

CONCLUSIONS:

These studies demonstrate that MyD88 deficiency in leukocytes profoundly reduces AngII-induced AAAs and atherosclerosis via mechanisms independent of either TLR2 or TLR4.

• Authors: A Phillip Owens 3rd, Debra L Rateri, Deborah A Howatt, Kathryn J Moore, Peter S Tobias, Linda K Curtiss, Hong Lu, Lisa A Cassis, Alan Daugherty
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 31 Issue 12 Pg. 2813-9 (Dec 2011) ISSN: 1524-4636 [Electronic] United States
• PMID: 21960563 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• Receptors, LDL
• Tlr2 protein, mouse
• Tlr4 protein, mouse
• Toll-Like Receptor 2
• Toll-Like Receptor 4
• Angiotensin II

Topics

• Angiotensin II (adverse effects)
• Animals
• Aortic Aneurysm, Abdominal (chemically induced, physiopathology, prevention & control)
• Apolipoproteins E (deficiency, genetics)
• Atherosclerosis (chemically induced, physiopathology, prevention & control)
• Disease Models, Animal
• Leukocytes (metabolism)
• Male
• Mice
• Mice, Knockout
• Myeloid Differentiation Factor 88 (deficiency, genetics, metabolism)
• Receptors, LDL (deficiency, genetics)
• Signal Transduction (physiology)
• Toll-Like Receptor 2 (deficiency, genetics, physiology)
• Toll-Like Receptor 4 (deficiency, genetics, physiology)