Chlamydia pneumoniae infection promotes a proliferative phenotype in the vasculature through Egr-1 activation in vitro and in vivo

Abstract

Atherosclerosis is characterized by inflammation and proliferation of vascular cells. The intracellular bacterium Chlamydia (Chlamydophila) pneumoniae uses blood monocytes [peripheral blood mononuclear cells (PBMCs)] for dissemination, has been found to persist in atherosclerotic lesions, and has been implicated in atherogenesis by small GTPase activation and T lymphocyte recruitment. Infection of human coronary artery smooth muscle cells with C. pneumoniae significantly induced mRNA and protein for the angiogenic transcription factor Egr-1, resulting in enhanced coronary artery smooth muscle cell proliferation, which was reduced by transfection with small interfering RNA duplexes targeted at Egr-1 mRNA. These effects required viable chlamydiae and depended on p44͞42 mitogen-activated protein kinase activity but not on the p38 mitogen-activated protein kinase pathway. Postinfectious Egr-1 mRNA up-regulation in arterial vessels was confirmed ex vivo in a rat aortic ring model of focal vascular chlamydial infection. An in vivo model based on the injection of C. pneumoniae-infected PBMCs into mice confirmed Egr-1 mRNA up-regulation within 24 h of endovascular infection. Arterial injury from repeated direct chlamydial infections and cell-to-cell contact with C. pneumoniae-infected PBMCs might represent a chronic focus of proliferative activity linked to the media proliferation seen in advanced atherosclerosis. Overall, chlamydial infection induces a proliferative phenotype in vascular cells via transcription factor Egr-1 activation in vitro, ex vivo, and in vivo.atherosclerosis ͉ cell proliferation T he comprehension of the pathogenesis of atherosclerosis has changed fundamentally. Models suggesting atherogenesis as a static accumulation of lipid-loaded macrophages and adherent thrombocytes were expanded by a more dynamic view of the mechanisms involved (1). Inflammation and proliferation of vascular smooth muscle cells were established as the central pathomechanisms (2), suggesting that injurious stimuli other than the known risk factors may initiate and trigger atherosclerosis. Epidemiological studies indicated that persistent infectious agents like Chlamydia (Chlamydophila) pneumoniae or herpesviruses might be involved in perpetuating coronary artery disease. Although diagnostic assays have produced controversial results on its frequency in vascular infection, C. pneumoniae remains the only replicative pathogen that has been recovered from atherosclerotic lesions, where it seems to be deposited by infected circulating blood monocytes (3-6). Vascular C. pneumoniae infection has recently been linked to the inflammatory and procoagulatory component of atherosclerosis by demonstrating small GTPase-mediated NF-B activation (7). Chlamydial heat-shock protein (8) and a soluble factor derived from infected endothelial cells are known to trigger smooth muscle cell proliferation (9). The molecular mechanisms leading to postinfectious proliferation of vascular cells, however, are unknown, although the entry into and the pro...

Lysophosphatidic Acid Induces Early Growth Response-1 (Egr-1) Protein Expression via Protein Kinase Cδ-regulated Extracellular Signal-regulated Kinase (ERK) and c-Jun N-terminal Kinase (JNK) Activation in Vascular Smooth Muscle Cells

“…It is important to note that Egr-1, a zinc finger transcription factor, plays a key master regulatory role in multiple cardiovascular pathological processes, including atherosclerosis, cardiac hypertrophy, ischemia, and angiogenesis (6), and was recently described as a major link between infection and atherosclerosis (32,33). Our data clearly establish a signaling pathway involving LPA 1 and the PKC␦-activated MAPK (ERK and JNK) cascade in regulating LPA induction of Egr-1 synthesis.…”

Host Cell Responses to Chlamydia pneumoniae in Gamma Interferon-Induced Persistence Overlap Those of Productive Infection and Are Linked to Genes Involved in Apoptosis, Cell Cycle, and Metabolism

“…For example, up-regulation of Egr-1 by chlamydiae was first identified by microarray and RT-PCR in HeLa cells in our laboratory (25). Meanwhile, this regulation has been confirmed for C. pneumoniae in vascular tissue (46). IFN-␥ induction, used in this study to identify such candidates in cell culture, is often considered a key model for chlamydial persistence and is certainly the best-studied one.…”

Chlamydia trachomatis Infection Induces Cleavage of the Mitotic Cyclin B1

“…The absence of an effect on cyclin B1 may explain why C. pneumoniae infection does not appear to be associated with a delay in host cell cycle progression (5,28). Rather, evidence points to the tendency of C. pneumoniae infection to actually stimulate vascular proliferation and remodeling (20,37). Perhaps this difference in the effect of C. trachomatis infection and that of C. pneumoniae infection on host cell cycle progression is partially responsible for the disparity in the types of diseases caused by these two organisms.…”