Wnt5a is expressed in murine and human atherosclerotic lesions

Abstract

Atherosclerosis is an inflammatory disease involving the accumulation of macrophages in the intima. Wnt5a is a noncanonical member of the Wnt family of secreted glycoproteins. Recently, human macrophages have been shown to express Wnt5a upon stimulation with bacterial pathogens in vitro and in granulomatous lesions in the lung of Mycobacterium tuberculosis-infected patients. Wnt5a expression has also been liked to Toll-like receptor-4 (TLR-4), an innate immune receptor implicated in atherosclerosis. These observations, along with the fact that Wnt5a is involved in cell migration and proliferation, led us to postulate that Wnt5a plays a role in atherosclerosis. To investigate this hypothesis, we characterized Wnt5a expression in murine and human atherosclerotic lesions. Tissue sections derived from the aortic sinus to the aortic arch of apolipoprotein E-deficient mice and sections derived from the carotid arteries of patients undergoing endarterectomy were subjected to immunohistochemical analysis. All samples were found to be positive for Wnt5a with predominant staining in the areas of macrophage accumulation within the intima. In parallel, we probed for the presence of TLR-4 and found coincident TLR-4 and Wnt5a expression. For both the Wnt5a and TLR-4 staining, consecutive tissue sections treated with an isotype- and species-matched Ig served as a negative control and exhibited little, if any, reactivity. Quantitative RT-PCR revealed that Wnt5a mRNA expression in RAW264.7 murine macrophages can be induced by stimulation with LPS, a known ligand for TLR-4. Combined, these findings demonstrate for the first time Wnt5a expression in human and murine atherosclerotic lesions and suggest that cross talk between TLR-4 and Wnt5a is operative in atherosclerosis.

Atherosclerotic Calcification: Wnt Is the Hint

“…A recent study has demonstrated a link between Wnt5a, toll‐like receptor 4, and pathological inflammation in human macrophages 124. Furthermore, the expression of Wnt5a has been demonstrated in murine and human atherosclerotic tissue 19. In addition to finding strong Wnt5a expression in macrophage‐rich regions of atherosclerotic lesions of apolipoprotein E–deficient mice on atherogenic diets, Wnt5a was also expressed in other regions of developed human plaques, such as in smooth muscle cells 19…”

“…They have a low proliferation rate that is maintained in check by the endothelium‐derived NO 12. Vascular injury triggers the phenotypic change to an active synthetic phenotype with an increased proliferation rate and secretory ability 19. Wnt signaling promotes VSMC survival,20 whereas silencing Wnt signaling reduces cell proliferation 21.…”

“…Adhesion of monocytes is considered the hallmark of atherosclerosis and considered atheromatous from this point forward 4. Dysfunction also alters endothelial permeability, allowing intraplaque invasion of monocytes and macromolecules, like low‐density lipoprotein 19. Under normal conditions, NO inhibits VSMC migration.…”

“…VC is a marker for atherosclerosis and is associated with several cardiovascular pathological features, including hypertension, congestive heart failure, cardiac hypertrophy, and ischemia, and increased risk of MI and stroke 38, 39. VC is a significant risk factor for morbidity and mortality in cardiovascular disease 7, 19, 37, 40, 41, 42, 43, 44. Once thought to be a passive degenerative process, it is now evident that biomineralization of the arterial wall is a complex regulated process 5, 45, 46.…”

Recombinant Wnt3a and Wnt5a elicit macrophage cytokine production and tolerization to microbial stimulation via Toll‐like receptor 4

“…The 19 mammalian homologues have distinct expression patterns in embryonic and adult tissues and their during infections with mycobacteria, Gram-negative and Grampositive bacteria [2][3][4][5][6], and chronic inflammation in rheumatoid arthritis, atherosclerosis, obesity, and psoriasis [7][8][9][10][11][12].…”