Title:Chronic Administration of Methamphetamine Aggravates
Atherosclerotic Vulnerable Plaques in Apolipoprotein E Knockout
Mice Fed with a High-cholesterol Diet
Volume: 24
Issue: 4
关键词:
甲基苯丙胺，易损斑块，神经肽Y，斑块内出血，二肽基肽酶IV，神经肽Y Y2受体。
摘要:
Background: It has been observed previously that chronic methamphetamine
(METH) administration could upregulate neuropeptide Y (NPY) expression and promote
atherosclerotic formation in apolipoprotein E knockout (ApoE-/-) mice fed with a normal
cholesterol or high diet and NPY might be involved in the pathogenesis of METHinduced
atherogenic effects through NPY Y1 receptor pathway. Vulnerable coronary
atherosclerotic plaque (VP) is a critical pathological finding responsible for the acute
coronary syndrome (ACS). In this study, we explored whether METH abuse could
aggravate the formation of VP in ApoE-/- mice fed with high cholesterol diet.
Objective: The purpose of this study was to observe if chronic METH administration
could aggravate vulnerable plaque (VP) formation in ApoE-/- mice fed with a highcholesterol
diet.
Methods: Male ApoE-/- mice fed with a high-cholesterol diet were intraperitoneally
injected with normal saline (NS) or 8 mg/kg/day METH (M8) for 24 weeks. Body weight
was monitored from baseline to 24 weeks at 2 weeks intervals. After 24 weeks of
treatment, plasma lipid variables were measured. Movat's staining and immunohistochemical
staining were performed on frozen sections of the aortic roots to calculate
VP percentage and intraplaque hemorrhage (IPH) percentage and detect expression of
NPY, vascular endothelial growth factor (VEGF), and CD31. In vitro, the expressions of
Y2R, VEGF, and CD31 were detected by immunofluorescence staining in aortic
endothelial cells incubated with PBS, 100μM METH, 10nmol NPY, or 100μM METH plus
10nmol NPY for 12 hours.
Results: The CD31 positive area, percentage of IPH, VP, and the expressions of NPY
and VEGF were significantly increased in the M8 group than in the NS group. In vitro,
the expressions of Y2R, VEGF, and CD31 were significantly increased in the
METH+NPY group than in the PBS, METH, and NPY groups and these effects could be
blunted by treatment with a Y2R antagonist or DPPIV inhibitor.
Conclusion: Chronic METH administration could aggravate VP in ApoE-/- mice fed with
a high-cholesterol diet, possibly through upregulating vascular NPY and VEGF
expression and promoting angiogenesis and vessel rupture in atherosclerotic plaques.
Our findings indicated that increased VP formation might contribute to the development
of acute coronary syndrome post-chronic METH abuse by activating DPPIV/NPY/Y2R
pathway.
