Rounding up the usual suspects in atherosclerosis. Focus on "Growth factors induce monocyte binding to vascular smooth muscle".

IN THE FILM “The Usual Suspects,” a group of criminals find themselves thrown together in a holding cell, where they hatch an elaborate plot that none of them alone could have executed. In studying the mechanisms of atherosclerosis, we tend to look at the suspects one by one, but it is clear that they work together to cause the disease. In the current article in focus (Ref. 3, see page C707 in this issue), Cai et al. have rounded up a large cadre of the usual suspects: the cell types of monocytes and vascular smooth muscle cells (VSMC), the growth factors angiotensin II (ANG II) and platelet-derived growth factor (PDGF), and the arachidonic acid (AA)-metabolizing enzymes 12/15-lipoxygenase (12/15-LO) and cyclooxygenase-2 (COX2). Importantly, they have placed their “suspects” in the context of vascular smooth muscle, not endothelium, to examine their potential role in monocyte retention (as opposed to recruitment) within the arterial wall. As the title of their article states, the interplay of these suspects in promoting monocyte binding in vascular smooth muscle has implications for atherosclerosis and warrants a reconsideration of the interactions between the key players as well as the anatomic locations of the pathological actions. It is abundantly clear that monocyte-macrophages and VSMC participate in the pathophysiology of atherosclerosis. The role of ANG II has also been extensively studied and is the subject of several recent reviews (e.g., Ref. 6). Human trials with ANG II receptor antagonists and inhibitors of ANG II formation have demonstrated improved endothelial function and decreases in myocardial infarction and stroke. Although a reduction in blood pressure can explain some of the clinical benefits seen in disruption of ANG II signaling, we and others have shown that ANG II has significant effects on atherosclerosis independent of blood pressure (16). In apolipoprotein E null mice (ApoE / ), ANG II treatment with a high-fat diet has a synergistic effect on lesion formation that is not shared by norepinephrine treatment at doses that produce the same degree of hypertension. The myriad effects of ANG II include the generation of oxidative stress via NADPH oxidases and the induction of a host of proinflammatory mediators. Cai et al. (3) propose additional effects on monocyte binding mediated by the release of soluble factors from VSMC, although further studies are required to establish the identity of these factors. Whereas human and animal studies employing blockade of ANG II signaling leave little doubt about its key role in atherosclerosis, the case for PDGF is less clear. Although PDGF has long been recognized as a potent stimulus of VSMC proliferation and migration, its role is more established in neointima formation following allograft transplantation or angioplasty than in atherogenesis. The lethality of knocking out PDGF signaling in mice has hindered a definitive assessment of its role in atherosclerosis, but some recent studies have managed to partially circumvent this obstacle. It appears that PDGF signaling in VSMC is normally held in check by the interaction of ApoE with low-density lipoprotein (LDL)-recep