Die Bedeutung von PACAP (Pituitary Adenylate Cyclase-Activating Polypeptide) bzw. seines Rezeptors PAC1 für die Entwicklung und Progression der Atherosklerose in 10 Wochen mit Cholesterin-gefütterten ApoE-defizienten Mäusen
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Philipps-Universität Marburg
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Abstract
The pituitary adenylate cyclase activating polypeptide (PACAP) acts via the
pleiotropically distributed G-protein coupled receptors PAC1, VPAC1 and
VPAC2. PAC1 is exclusively activated by PACAP. In contrast, VPAC1 and
VPAC2 can also be activated by the related vasoactive intestinal peptide (VIP).
PACAP acts, among other organ systems, on blood vessels, immune cells and
the neuroendocrine system. The present study investigated the in vivo effect of a
PACAP or PAC1 deficiency (PACPAP-/- or PAC1-/-) on the development and
course of atherosclerosis in the apolipoprotein E knockout (ApoE-/-) mouse model
after 10 weeks standard food (SF) and then 10 weeks on a cholesterol enriched
diet (CRF). The genotypes ApoE-/-, PACAP-/- / ApoE-/- and PAC1-/- / ApoE-/- were
examined. Mice were weighed, their plasma cholesterol and triglyceride
concentrations were measured. The truncus brachiocephalicus (TB) was then
removed and immediately shock frozen in liquid nitrogen-cooled isopentane.
Frozen sections were prepared from the TB and used to quantify luminal stenosis,
morphological, remodeling, and inflammatory parameters. Mean body weights
were similar in all genotypes, however, the tibiae in PACAP-/-/ApoE-/-- mice were,
on average, significantly 1.1-fold longer than that of ApoE-/-- mice. The plasma
cholesterol and triglyceride levels of the three genotypes examined were similar.
In PACAP-/- / ApoE-/-- mice, mean luminal stenosis was significantly 1.5-fold less
than in ApoE-/-- mice. In addition, we found a significantly 1.5-fold smaller
percentage of sm-α-actin-positive plaque area in this genotype. On the other
hand, the percentage of Ki-67-positive cell nuclei was significantly 2.6 times
greater than in the ApoE-/-- control. In addition, the percentage of interleukin-6
positive plaque area was significantly 1.6-fold higher than in ApoE-/- mice.
Lumen stenosis was also significantly 4.3-fold lower in PAC1-/- / ApoE-/-- mice
than in ApoE-/-- mice. Furthermore, in PAC1-deficient mice, the percentage of
MoMa-2-positive plaque area was significantly 5.8-fold smaller than in ApoE-/-
mice. Additionally, the percentage of ATG5-positive plaque area was significantly
2.2-fold smaller than in ApoE-/- mice.
Overall, both PACAP-/- and PAC1-/- mice showed anti-atherosclerotic effects
compared to controls (ApoE-/-). In addition, a lower proportion of myocytes was
observed, which could result in reduced plaque stability. In PACAP-/- / ApoE-/--
mice there was also evidence of enlarged proliferation activity in the form of a
larger percentage of Ki-67-positive cell nuclei and increased inflammation in the
plaque areas. PAC1 deficiency also resulted in reduced monocyte and
macrophage density and a lower proportion of ATG5-positive areas in the plaque.
Our results confirm and extend the findings of others, i.e. the existing assumption
of an effect of PACAP or PAC1 on the development and progression of
atherosclerosis could be additionally strengthened by our study. Interestingly, in
addition to previously published data, a reduced lumen stenosis due to PACAP
or PAC1 deficiency after CRF was shown. The supposedly protective effect of
PACAP could therefore also be mediated via the VPAC1 and VPAC2 receptors.
The complex and diverse effects of PACAP and its receptors should be
investigated in further studies in order to better understand the underlying
molecular mechanisms in the respective organ systems. Based on our results
and the data available so far, future studies should show whether the
development and progression of atherosclerosis can be positively influenced by
the pharmacological use of PACAP receptor modulators, such as synthetic
PACAP38 or Maxadilan.
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Dates
Created: 2022Issued: 2023-07-26Updated: 2023-07-28
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
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DoctoralThesis
DFG-subjects
AtherosklerosePAC1PACAP
DDC-Numbers
610
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Neudert, Philip: Die Bedeutung von PACAP (Pituitary Adenylate Cyclase-Activating Polypeptide) bzw. seines Rezeptors PAC1 für die Entwicklung und Progression der Atherosklerose in 10 Wochen mit Cholesterin-gefütterten ApoE-defizienten Mäusen. : Philipps-Universität Marburg 2023-07-26. DOI: https://doi.org/10.17192/z2023.0027.