Biology Reference
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was an active participant in the disease process (Gyorkey et al. 1984). A study of
atheromatous tissue from patients with restenosis following angioplasty for coronary
artery atherosclerotic disease also demonstrated HCMV nucleic acids in a significant
number of specimens, and more recent studies have shown that HCMV infection is
more efficient in atherosclerotic blood vessels (Speir et al. 1994; Nerheim et al.
2004; Westphal et al. 2006). In one study, smooth muscle cells isolated from athero-
sclerotic plaques often contained cytoplasmic p53 and the protein product of the IE-2
gene of HCMV, findings consistent with the interpretation that HCMV IE-2 inhibited
the normal functions of p53 in smooth muscle cells (Speir et al. 1994). This led to the
hypothesis that HCMV could promote atherosclerotic vascular disease by inducing
smooth muscle cell proliferation through its interaction with p53, particularly if
mitogenic signals provided by growth factors and cytokines were also present as a
result of ongoing inflammation and the accumulation of circulating mononuclear
cells (Libby et al. 1988a, 1988b; Speir et al. 1994; Zhou et al. 1999). Subsequent
studies from other laboratories have demonstrated inactivation of p53 function fol-
lowing HCMV infection and an anti-apoptotic effect provided by IE-2 expression
(Zhu et al. 1995; Kovacs et al. 1996). It should be noted that a later study of diseased
coronary arteries also detected HCMV nucleic acids in plaques in six of 13 specimens
but detected cytoplasmic p53 in only two of 19 of specimens from the same study
(Baas et al. 1996). Other mechanisms that have been proposed for the contribution of
HCMV infection to arteriosclerosis include induction of expression of adhesion
molecules such as ICAM-1 and growth factors such a PDGF and TGF by HCMV
infection, elevation of IL-6 levels, induction of chemokine expression by endothelial
cells, and endothelial cell dysfunction (Blankenberg et al. 2001; Grahame-Clarke
et al. 2003; Petrakopoulou et al. 2004; Reinhardt et al. 2005; Westphal et al. 2006).
Subintimal infiltration by smooth muscle cells has been reported to be a critical
feature of the arterial narrowing observed in atherosclerotic disease and in trans-
plant vascular sclerosis, and when viewed together with the concept that atherosclerotic
vascular disease is an inflammatory disease suggested several potential roles for
HCMV in this disease (Lemstrom et al. 1993; Kloppenburg et al. 2005). Streblow
and colleagues have reported that smooth muscle cells expressing the HCMV-
encoded chemokine receptor, US28, will migrate in response to a CC chemokine
gradient and in a rat model of transplant vascular sclerosis; similarly, the rat CMV
encoded chemokine receptor, R33, has been shown to play a role in disease devel-
opment presumably by acting as a chemoattractant for smooth muscle cell migration
(Streblow et al. 1999; Melnychuk et al. 2005). Chemokines that have been shown
to induce responses from US28 expressed in HCMV-infected cells include
RANTES and MCP-1, both of which can be produced by resident macrophages and
infiltrating mononuclear cells present within an inflammatory focus associated with
an atheromatous plaque (Streblow et al. 1999). These findings together with previous
observations that described increased expression of cell adhesion molecules such as
ICAM-1 in endothelial cells infected with HCMV suggested that adherence of
circulating mononuclear cells could initiate an inflammatory cascade leading to
directional migration of HCMV-infected smooth muscle cells, subintimal thickening
and arterial narrowing (Span et al. 1991; Sedmak et al. 1994; Yilmaz et al. 1996;
