The incretin hormone GIP is upregulated in patients with atherosclerosis and stabilizes plaques in ApoE−/− mice by blocking monocyte/macrophage activation

Abstract

ObjectiveThe incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) are secreted by the gut after food intake leading to pancreatic insulin secretion and glucose lowering. Beyond its role in glucose control, GLP-1 was found in mice and men to beneficially modulate the process of atherosclerosis, which has been linked to improved cardiovascular outcome of patients with diabetes at high cardiovascular risk treated with GLP-1 receptor agonists. However, little is known on the role of the other main incretin in the cardiovascular system. The aim of this study was to characterize GIP in atherosclerotic cardiovascular disease.Methods and resultsSerum concentrations of GIP were assessed in 731 patients who presented for elective coronary angiography at the University Hospital Aachen. While GIP concentrations were not associated with coronary artery disease (CAD), we found 97 patients with PAD (peripheral artery disease) vs. 634 without PAD to have higher circulating GIP levels (413.0 ± 315.3 vs. 332.7 ± 292.5 pg/mL, p = 0.0165). GIP levels were independently related to PAD after multivariable adjustment for CAD, age, sex, BMI, hypertension, diabetes, CRP, WBC, and smoking. To investigate the functional relevance of elevated GIP levels in human atherosclerotic disease, we overexpressed GIP (1–42) in ApoE−/− mice fed a Western diet for 12 weeks using an adeno-associated viral vector system. GIP overexpression led to reduced atherosclerotic plaque macrophage infiltration and increased collagen content compared to control (LacZ) with no change in overall lesion size, suggesting improved plaque stability. Mechanistically, we found GIP treatment to reduce MCP-1-induced monocyte migration under In vitro conditions. Additionally, GIP prevented proinflammatory macrophage activation leading to reduced LPS-induced IL-6 secretion and inhibition of MMP-9 activity, which was attributable to GIP dependent inhibition of NfκB, JNK-, ERK, and p38 in endotoxin activated macrophages.ConclusionElevated concentrations of the incretin hormone GIP are found in patients with atherosclerotic cardiovascular disease, while GIP treatment attenuates atherosclerotic plaque inflammation in mice and abrogates inflammatory macrophage activation in vitro. These observations identified GIP as a counterregulatory vasoprotective peptide, which might open new therapeutic avenues for the treatment of patients with high cardiovascular risk.

GIP as a Potential Therapeutic Target for Atherosclerotic Cardiovascular Disease–A Systematic Review

“…This suggests the involvement of GIPR/adenyl cyclase/PKA axis. The anti-inflammatory effects of GIP on monocytes were further demonstrated by a recent study showing that active GIP suppressed the chemokine ligand 2 (CCL2)-induced migration of mouse monocyte RAW 264 cells and human monocyte THP-1 cells thorough reductions in gene expression levels of chemokine receptor type 2 [77]. In addition, active GIP also inhibited the matrix metalloproteinase-9 protein levels and interleukin (IL)-6 production by suppressing LPS-induced activation of nuclear factor-kappa B p65 and mitogen-activated protein kinases in mouse monocyte RAW 264 cells [77].…”

“…Indeed, a couple of studies showed the anti-inflammatory effects of GIP in immune cells (Table 1) [76,77]. GIP ranging from 1 to 100 nM dose-dependently suppressed the lipopolysaccharide (LPS)-induced gene expression levels of tumor necrosis factor (TNF) or inducible NOS in human monocyte THP-1 cells, and these effects were abolished by inhibiting adenyl cyclase or PKA, but not exchange protein directly activated by cAMP 2 [76].…”

“…Atherosclerosis is the main cause of tissue ischemia and infarction in brains and hearts, and its prevention has long been a potential therapeutic target to suppress the CVD in individuals with diabetes [1,2]. Anti-atherogenic effects of GIP in mouse models were reported by several research groups (Table 2) [19,21,77]. We have found in atherosclerosis-prone apolipoprotein E knockout (ApoE-/-) mice [95] that chronic infusion of active GIP (25 nmol/kg/day) for 4 weeks suppresses the aortic plaque formation and intra-plaque macrophage accumulation compared with vehicle treatment, whose effects were totally independent of food intake, body weight, systolic blood pressure, and plasma glucose and lipid levels [19].…”

“…The infusion of active GIP (25 nmol/kg/day) for 4 weeks reduced the aortic plaque formation, intra-plaque macrophage accumulation, macrophage foam cell formation in streptozotocin-induced diabetic ApoE-/mice. In addition, recently, overexpression of GIP has been reported to stabilize the atherosclerotic plaque in non-diabetic ApoE-/mice [77]; overexpression of GIP gene reduced macrophage accumulation and increased collagen content of aortic plaques, while it did not induce body weight gain. Taken together, these findings suggest that GIP at pharmacological concentrations could exert protective effects against atherosclerosis without deteriorating the obesity, and the beneficial effects of GIP might also be preserved in diabetic animals.…”

Evaluation of a rare glucose‐dependent insulinotropic polypeptide receptor variant in a patient with diabetes

“…25 In addition to these effects in β cells and adipose tissue, GIP/GIPR has been reported to have various effects on metabolic and cardiovascular diseases. GIP/GIPR agonism is vasoprotective in atherosclerosis patients, 26 whereas, in contrast, disruption of GIP/GIPR is beneficial after myocardial infarction. 27 These findings broaden the system that needs to be considered when developing new drugs that modulate the GIP/GIPR axis.…”