Role of Histamine Produced by Bone Marrow–Derived Vascular Cells in Pathogenesis of Atherosclerosis

Abstract

Abstract-To clarify the role of histamine-producing cells and its origin in atherosclerosis, we investigated histidine decarboxylase (HDC; histamine-producing enzyme) expression in murine arteries with vascular injuries after the animal had received transplanted bone marrow (BM) from green fluorescent protein (GFP)-transgenic mice. The neointima in the ligated carotid arteries contained BM-derived HDC ϩ cells that expressed macrophage (Mac-3) or smooth muscle cell antigen (␣-SMA). In contrast, the HDC ϩ BM-derived cells, which were positive for Mac-3, were mainly located in the adventitia in the cuff replacement model. In apolipoprotein E-knockout mice on a high cholesterol diet, BM-derived cells expressing Mac-3 in the atheromatous plaques were also positive for HDC. In comparison with wild-type mice, HDC Ϫ/Ϫ mice showed reduced neointimal thickening and a decreased intima-to-media ratio after ligation and cuff replacement. These results indicate that histamine produced from BM-derived progenitor cells, which could transdifferentiate into SMC-or macrophage-like cells, are important for the formation of neointima and atheromatous plaques. Key Words: histamine Ⅲ histidine decarboxylase Ⅲ progenitor cells Ⅲ bone marrow Ⅲ vascular injury H istidine decarboxylase (HDC) is a rate-limiting enzyme for the production of histamine from L-histidine. Histamine plays an important role in allergy, inflammation, neurotransmission, and gastrointestinal functions by acting via specific histamine receptors. 1,2 With regards to the atherosclerotic coronary artery, histamine is a vasoconstrictor, and the accumulation of activated mast cells in the adventitia and ruptured plaques in acute coronary syndrome has been reported. [3][4][5] Another histamine-producing cell in the atherosclerotic lesion is the macrophage, 6 which is present in all stages of atherosclerosis and is a major cellular constituent of atheromatous plaques. Previously, we demonstrated that HDC is expressed in CD68 ϩ foam cells (macrophages) of human atherosclerotic lesions. 6 In monocytic human U937 cells, the expression of HDC and histamine H1 receptor (HH1R) is induced during macrophage differentiation, 6,7 and granulocyte macrophage-colony stimulating factor, one of the proinflammatory and macrophage-differentiation factors produced in the atherosclerotic lesions, 8 is also able to induce HDC and HH1R. 9 As a longer-term effect, histamine stimulates cultured human intimal smooth muscle cells (SMCs) to proliferate and to express matrix metalloproteinase-1 (MMP-1). 10 Histamine also upregulates the gene expression of endothelial nitric oxide synthase (eNOS) in vascular endothelial cells (ECs). 11 These histamine effects are all mediated via HH1R, which is expressed in the ECs, foam cells, and SMCs of human atherosclerotic lesions. 12 In the case of monocytes, we have reported that histamine upregulates lipopolysaccharideinduced expression of tumor necrosis factor-␣ (TNF-␣) during macrophage differentiation and switching of the histamine receptor from histamine H...

Histamine Induces Egr-1 Expression in Human Aortic Endothelial Cells via the H1 Receptor-mediated Protein Kinase Cδ-dependent ERK Activation Pathway

“…One of these studies showed that the histamine H1 receptor antagonist reduced intimal hyperplasia (13); the other study reported that histamine synthesis enzyme knock-out mice (HDC Ϫ/Ϫ mice) showed reduced neointimal thickening and a decreased intima-to-media thickness ratio (14). In regard to how histamine influences inflammation and atherosclerosis in endothelial cells, evidence has shown that histamine induces expression of genes such as p-selectin (9), ICAM1, VCAM1 (10), IL6, IL8 (8), cyclooxygenase-2 (27), and tissue factor (11).…”

“…Histamine also induces tissue factor expression in smooth muscle cells (11), and smooth muscle cell proliferation (12,13). Most importantly, the antagonists of histamine receptor 1 (H1) reduce thickened intimas in mice (13), and recently, HDC knock-out mice showed reduced neointimal thickening (14). All of this accumulating evidence supports the notion that histamine promotes the development and progression of atherosclerosis.…”

Histamine differentially interacts with tumor necrosis factor‐α and thrombin in endothelial tissue factor induction: the role of c‐Jun NH2‐terminal kinase

“…A pathogenetic role of histamine in atherogenesis was highlighted by recent studies demonstrating that histidine decarboxylase as well as the H 1 -receptor are expressed in atherosclerotic human arteries [11], and that mice deficient in histidine decarboxylase exhibit reduced intimal thickening after vascular injury [10]. Invasion and activation of leukocytes are early events in atherogenesis.…”

Overexpression of Peroxiredoxin 4 Attenuates Atherosclerosis in Apolipoprotein E Knockout Mice

“…Considering our finding that the SMCs in the advanced atherosclerotic lesions of hPRDX4 + / + /apoE -/ -mice showed very low proliferative activity based on MIB-1 staining, the activated PDGF expression and secretion would enhance SMC migration, particularly in the thickened fibrous caps of atheromatous plaques, and may therefore reduce plaque vulnerability in hPRDX4 + / + / apoE -/ -mice. Accordingly, overexpression of hPRDX4 might be closely related to PDGF-induced migratory signaling in neointimal SMCs, the possible origins of which could include PRDX4-expressed medial SMCs, circulating SMC precursor cells, or adventitial SMC progenitor cells (19,20,32).…”