Glucagon-Like Peptide-1 Receptor Activation Does Not Affect Re-Endothelialization but Reduces Intimal Hyperplasia via Direct Effects on Smooth Muscle Cells in a Nondiabetic Model of Arterial Injury

Eriksson, Linnéa; Saxelin, Robert; Röhl, Samuel; Roy, Joy; Caidahl, Kenneth; Nyström, Thomas; Hedin, Ulf; Razuvaev, Anton

doi:10.1159/000381097

Cited by 25 publications

(21 citation statements)

References 50 publications

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“…Studies in experimental animals have demonstrated that liraglutide accelerates endothelial recovery after injury (41), retards atheroma formation in apolipoprotein E knockout mice (42), exerts anti-inflammatory effects on the vasculature, and inhibits reactive oxygen species formation and platelet aggregation (43). Collectively, these actions of GLP-1 RAs could slow the atherosclerotic process.…”

Section: Potential Mechanisms To Explain CV Benefitmentioning

confidence: 99%

Cardiovascular Disease and Type 2 Diabetes: Has the Dawn of a New Era Arrived?

et al. 2017

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Hyperglycemia is the major risk factor for microvascular complications in patients with type 2 diabetes (T2D). However, cardiovascular disease (CVD) is the principal cause of death, and lowering HbA1c has only a modest effect on reducing CVD risk and mortality. The recently published LEADER and SUSTAIN-6 trials demonstrate that, in T2D patients with high CVD risk, the glucagon-like peptide 1 receptor agonists liraglutide and semaglutide reduce the primary major adverse cardiac events (MACE) end point (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke) by 13% and 24%, respectively. The EMPA-REG OUTCOME, IRIS (subjects without diabetes), and PROactive (second principal end point) studies also demonstrated a significant reduction in cardiovascular events in T2D patients treated with empagliflozin and pioglitazone. However, the benefit of these four antidiabetes agents (liraglutide, semaglutide, empagliflozin, and pioglitazone) on the three individual MACE end points differed, suggesting that different underlying mechanisms were responsible for the reduction in cardiovascular events. Since liraglutide, semaglutide, pioglitazone, and empagliflozin similarly lower the plasma glucose concentration but appear to reduce CVD risk by different mechanisms, there emerges the intriguing possibility that, if used in combination, the effects of these antidiabetes agents may be additive or even multiplicative with regard to cardiovascular benefit.

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Section: Potential Mechanisms To Explain CV Benefitmentioning

confidence: 99%

Cardiovascular Disease and Type 2 Diabetes: Has the Dawn of a New Era Arrived?

et al. 2017

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“…The results of the present study demonstrated no increase of cAMP upon increasing the GIP concentration at high glucose levels, but GLP-1 increased the cAMP concentration proportional to its concentration. A previous study indicated that there was a significant decrease in proliferation and an increase in the apoptosis of smooth muscle cells in vitro following treatment with exendin-4, this effect appears to be mediated through cAMP signaling (23). Ge et al (24) demonstrated the protective effect of GLP-1 using microvascular endothelial cells whereas the present study used HUVEC as a macrovascular cell line.…”

Section: Discussionmentioning

confidence: 61%

Difference in protective effects of GIP and GLP-1 on endothelial cells according to cyclic adenosine monophosphate response

Lim

Park

Hwang

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Receptors for glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are present in vascular endothelial cells. Previous studies investigating euglycemic status have demonstrated that GIP is directly involved in the physiology of blood vessels by controlling the blood flow rate of portal veins and that GLP-1 has a protective effect on blood vessels by acting on endothelial cells. However, to the best of our knowledge, the effects of GIP and GLP-1 on endothelial cells in patients with hyperglycemia remain unknown. Therefore, the present study investigated whether the effect of the incretin hormones GLP-1 and GIP differed with regards to the reversal of endothelial cell dysfunction caused by hyperglycemia. The production of nitric oxide (NO) was measured using the Griess reagent system kit and the expression of cyclic adenosine monophosphate (cAMP) in the cell was measured at a wavelength of 405 nm with the ELISA reader using the cyclic AMP EIA kit. Exposure of human umbilical vein endothelial cells (HUVEC) to a high glucose concentration decreased NO and endothelial nitric oxide synthase (eNOS) levels but increased inducible NOS (iNOS) levels. However, when HUVECs were pretreated with GLP-1, a reduction of iNOS expression was observed and the expression of eNOS and NO were increased, as opposed to pretreatment with GIP. The results differed according to the response of cAMP, the second messenger of incretin hormones: The GIP pretreatment group did not exhibit an increase in cAMP levels while the GLP-1 pretreatment group did. The results of the present study provide evidence that GLP-1, but not GIP, has a protective effect on endothelial function associated with cardiovascular disease, as it is associated with increased eNOS expression and the levels of NO. This effect may be due to an increase in the cAMP concentration during hyperglycemic events.

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“…In wild‐type mice, exendin‐4(Ex‐4), a GLP‐1 receptor agonist, reduces neointimal hyperplasia after femoral artery wire injury without affecting the metabolic parameters, including glucose tolerability. Similarly, Ex‐4 showed a protective effect against neointimal hyperplasia with reduced VSMC proliferation in a rat model of restenosis. Furthermore, in vitro studies show supportive data that Ex‐4 suppressed rat VSMC proliferation stimulated by platelet‐derived growth factor.…”

Section: Incretins and Dpp‐4 Inhibitors Suppress Neointimal Hyperplasmentioning

confidence: 91%

Anti‐atherogenic and anti‐inflammatory properties of glucagon‐like peptide‐1, glucose‐dependent insulinotropic polypepide, and dipeptidyl peptidase‐4 inhibitors in experimental animals

Hirano

Mori

2016

J of Diabetes Invest

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We reported that native incretins, liraglutide and dipeptidyl peptidase‐4 inhibitors (DPP‐4i) all confer an anti‐atherosclerotic effect in apolipoprotein E‐null (Apoe −/−) mice. We confirmed the anti‐atherogenic property of incretin‐related agents in the mouse wire injury model, in which the neointimal formation in the femoral artery is remarkably suppressed. Furthermore, we showed that DPP‐4i substantially suppresses plaque formation in coronary arteries with a marked reduction in the accumulation of macrophages in cholesterol‐fed rabbits. DPP‐4i showed an anti‐atherosclerotic effect in Apoe −/− mice mainly through the actions of glucagon‐like peptide‐1 and glucose‐dependent insulinotropic polypepide. However, the dual incretin receptor antagonists partially attenuated the suppressive effect of DPP‐4i on atherosclerosis in diabetic Apoe −/− mice, suggesting an incretin‐independent mechanism. Exendin‐4 and glucose‐dependent insulinotropic polypepide elicited cyclic adenosine monophosphate generation, and suppressed the lipopolysaccharide‐induced gene expression of inflammatory molecules, such as interleukin‐1β, interleukin‐6 and tumor necrosis factor‐α, in U937 human monocytes. This suppressive effect, however, was attenuated by an inhibitor of adenylate cyclase and mimicked by 8‐bromo‐cyclic adenosine monophosphate or forskolin. DPP‐4i substantially suppressed the lipopolysaccharide‐induced expression of inflammatory cytokines without affecting cyclic adenosine monophosphate generation or cell proliferation. DPP‐4i more strongly suppressed the lipopolysaccharide‐induced gene expression of inflammatory molecules than incretins, most likely through inactivation of CD26. Glucagon‐like peptide‐1 and glucose‐dependent insulinotropic polypepide suppressed oxidized low‐density lipoprotein‐induced macrophage foam cell formation in a receptor‐dependent manner, which was associated with the downregulation of acyl‐coenzyme A cholesterol acyltransferase‐1 and CD36, as well as the up‐regulation of adenosine triphosphate‐binding cassette transporter A1. Our studies strongly suggest that incretin‐related agents have favorable effects on macrophage‐driven atherosclerosis in experimental animals.

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Glucagon-Like Peptide-1 Receptor Activation Does Not Affect Re-Endothelialization but Reduces Intimal Hyperplasia via Direct Effects on Smooth Muscle Cells in a Nondiabetic Model of Arterial Injury

Cited by 25 publications

References 50 publications

Cardiovascular Disease and Type 2 Diabetes: Has the Dawn of a New Era Arrived?

Cardiovascular Disease and Type 2 Diabetes: Has the Dawn of a New Era Arrived?

Difference in protective effects of GIP and GLP-1 on endothelial cells according to cyclic adenosine monophosphate response

Anti‐atherogenic and anti‐inflammatory properties of glucagon‐like peptide‐1, glucose‐dependent insulinotropic polypepide, and dipeptidyl peptidase‐4 inhibitors in experimental animals

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