The incretin hormone GIP decreases vascular infiltration and proinflammatory activation of monocytes in ApoE-/- mice

 

Purpose:

Activation of the GLP-1-System (Glucagon-like-peptide-1) has been shown to prevent the development of atherosclerosis in experimental models and to reduce cardiovascular mortality in patients with diabetes. Recent evidence also suggested anti-atherosclerotic effects of the other main incretin GIP (glucose-dependent insulinotropic peptide) in mice, however with yet elusive mechanism.

Methods and Results:

In our study GIP and LacZ were overexpressed in ApoE^-/- mice fed a high-fat diet for 12 weeks using an adeno-associated viral vector system (n = 9 – 10/group). GIP overexpression had no effect on body weight, lipid profile and glucose tolerance, but led to significantly reduced plaque macrophage infiltration (GIP 7,1% vs. LacZ 13,1% MOMA-2 expression per lesion area, p < 0.05) compared to LacZ at the aortic root with no change of overall lesion size. Consistent with our in vivo results we found GIP incubation to reduce MCP-1-induced migration of monocytes in vitro, which was paralleled by decreased expression of VCAM-1 and ICAM-1 in VSMC (vascular smooth muscle cells). In addition, GIP inhibited proinflammatory activation of macrophages as shown by a reduction of LPS-induced NfκB activation as well as IL-6 and TNF-α secretion. Furthermore, GIP decreased TNF-α-induced MMP-2/-9 expression in VSMC in vitro, suggesting a possible protective role of GIP in inflammation-induced vascular remodeling.

Conclusion:

Overexpression of GIP attenuated vascular inflammation and MMP expression, suggesting improved inflammation-induced vascular matrix remodeling following GIP treatment. Therefore, activation of the GIP-System might provide a novel approach for the treatment of pathological vascular remodeling in cardiovascular disease.