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The early development of atherosclerosis after perinatal inflammation

(2012) Dees, C.J. (Christiaan)

Background:
Atherosclerosis with thrombosis is the leading cause of death and severe disability worldwide. Even though well-known risk factors account for most heart attacks, the individual susceptibility varies greatly and this makes prediction difficult. It is believed that the underlying pathology begins before or soon after birth and develops throughout life until it becomes clinically noticeable. Early life is therefore a largely overlooked period for preventive strategies. It is necessary to understand the factors that control the initiation and development of atherosclerosis in utero and childhood, in order to identify periods that might provide opportunities for intervention.
It is known that atherosclerosis is a chronic inflammatory condition, but the factors that activate and stimulate this process still remain mostly unidentified.
Hypothesis:
We hypothesise that intrauterine inflammation accelerates the development and severity of atherosclerosis.
Aim:
Our aim is to establish the effect of intrauterine inflammation on the development and severity of atherosclerosis, and to identify the underlying mechanisms, in genetically predisposed mice.
Methods:
Pregnant mice lacking apolipoprotein E received intra-amniotic injections (5µl) of saline or lipopolysaccharide (LPS, 0.1ng) at 15.5 days of gestation (term is 19 days). On day 17.5, 1 pregnancy from each group was used for collection of fetal tissues and placentae (saline, n=8; LPS, n=6). Immunohistochemical staining of the leukocyte antigen CD45 was used to evaluate placental inflammation. Remaining mice were left to deliver their litters spontaneously at term. Pups were weaned at 4 weeks and placed on a high (22%) fat diet until collection of the heart and aorta at 6 weeks (saline, n=5; LPS, n=5). Total cholesterol and cholesterol ester levels in aortic tissue were measured by enzymatic conversion assay and UV spectroscopy, respectively.
Results:
Placental leucocyte infiltration was increased in placentae from mothers in the LPS-treated group compared to Saline (control)-treated mothers (p=0.028). Furthermore, total cholesterol and cholesterol ester levels in aortic and cardiac tissues from pups born out of LPS-treated mothers were increased compared to pups born from saline-treated mothers(p<0.05).
Conclusions:
Our data indicate that intrauterine inflammation increases aortic and cardiac cholesterol and cholesterol ester accumulation in the offspring, which may accelerate the development of atherosclerosis in adult life.





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