Background:
Endothelin (ET)-1 plays an important role in generation of reactive oxygen species (ROS) and inflammation in the vasculature. ET-1has been implicated in the pathogenesis of atherosclerosis since plasma and tissue ET-1 are increased in human and animal models of atherosclerosis. We observed that ET-1 overexpression exacerbates high-fat diet (HFD)-induced atherosclerosis in
apolipoprotein E
knockout (
apoE
-/-
) mice. We hypothesized that ET-1-induced ROS and inflammation contribute to the development of atherosclerosis.
Design and methods:
Eight-week-old male transgenic mice overexpressing preproET-1 in the endothelium (eET-1),
apoE
-/-
, eET-1/
apoE
-/-
and wild type mice were fed a HFD for 8 weeks. Aortic atherosclerotic lesions were quantified using Oil Red O staining. ROS production using dihydroethidium staining and monocyte/macrophage and T cell infiltration using immunofluorescence with MOMA-2 and anti-CD4 antibodies, respectively, were determined in perivascular fat, media and plaque in ascending aortic sections.
Results:
eET-1/
apoE
-/-
presented 3.8-fold more atherosclerotic lesions in whole aorta compared to
apoE
-/-
(
P
<0.01). ET-1 overexpression caused 2.6-, 1.9- and 1.9-fold increase in ROS production in perivascular fat, media and plaque of
apoE
-/-
, respectively (
P
<0.05). ET-1 overexpression increased monocyte/macrophage infiltration by 5- and 8-fold in perivascular fat and media, respectively (
P
<0.05). CD4
+
T cell infiltration was observed in perivascular fat and plaque of 3 and 5 of 6 eET-1/
apoE
-/-
compared to 0 and 1 of 6
apoE
-/-
, respectively (
P
<0.05).
Conclusions:
These results suggest that ET-1 play an important role in progression of atherosclerotic lesions by increasing the oxidative stress and monocyte/macrophage and T cell infiltration in the atherosclerotic aorta, including the perivascular fat.
Endothelin-1-induced oxidative stress and inflammatory cell infiltration contribute to high-fat diet induced-atherosclerosis and aneurysm formation in apolipoprotein E knockout mice