Activation of VPAC1 receptors aggravates early atherosclerosis in hypercholesterolemic apolipoprotein E-deficient mice.
OBJECTIVE
Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide widely expressed in the body and binding three types of receptors: VPAC(1)-R, VPAC(2)-R and PAC(1)-R. Based on beneficial effects of VIP and VPAC(1)-R agonists in mouse models of several chronic inflammatory disorders, we hypothesized that activation of VIP receptors would prevent atherosclerosis development in apolipoprotein E-deficient mice.


RESULTS
Contrary to our hypothesis, administration of a VPAC(1)-R agonist, (Ala(11,22,28))-VIP aggravated atherosclerotic lesion development in the aortic root of these mice compared to control mice. This was accompanied by a significant increase in the expression of MHC class II protein I-A(b), and suggests enhanced inflammatory activity in the vessel wall. The amount of macrophage-specific CD68 staining as well as serum cholesterol and triglyceride levels did not change as a result of the (Ala(11,22,28))-VIP treatment, i.e. the treatment resulted in significant changes in lipid accumulation in the lesions without changing the number of macrophages or systemic lipid levels. Interestingly, administration of VIP did not alter the course of the disease.


CONCLUSIONS
Despite beneficial effects in murine models of several inflammatory disorders, VPAC(1)-R activation aggravates atherosclerotic lesion formation in apolipoprotein E-deficient mice through enhanced inflammatory activity in the vessel wall.
Experimental Cardiovascular Research Unit, Center for Molecular Medicine, Department of Medicine at Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden. yuri.sheikine@ki.se
Yuri
Y
Sheikine
Barbara
B
Deodato
Peder S
PS
Olofsson
Leif A
LA
Söderström
Anna M
AM
Lundberg
Inger
I
Bodin
Mats
M
Rudling
Elvar
E
Theodorsson
Göran K
GK
Hansson
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control; D001402:B-Lymphocytes / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000819:agonists; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000819:agonists*; D013154:Spleen / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects; D014660:Vasoactive Intestinal Peptide / Q000097:blood / Q000494:pharmacology
D001057:Apolipoproteins E; D016207:Cytokines; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D014660:Vasoactive Intestinal Peptide