Glucagon-like peptide-1 (GLP-1) and its split products GLP-1(9-37) and GLP-1(28-37) stabilize atherosclerotic lesions in apoe−/− mice
Introduction
Glucagon-like peptide-1 (GLP-1) based therapies are a new group of anti-diabetic drugs which improve glucose metabolism by increasing glucose dependent insulin secretion while suppressing glucagon release from pancreatic islet cells [1]. GLP-1 reduces gastric motility, suppresses appetite and has potent athero- and cardioprotective effects [2]. Bioactivity of GLP-1 is however limited to approximately 2 min due to a rapid DPP-IV dependent degradation via cleavage of the first two amino-acids of the peptide [1]. The thereby created GLP-1(9-37) does not stimulate the GLP-1 receptor but rather acts as a week antagonist [1]. Further degradation of GLP-1 is reached by neutral endopeptidase dependent cleavage at the c-terminus of the peptide creating the additional split products GLP-1(28-37) and GLP-1(32-37) [3].
GLP-1 based therapies take advantage of longer acting agonists of the GLP-1 receptor or inhibitors of dipeptidyl peptidase-IV (DPP-IV) which increase the bioavailability of endogenous GLP-1. As patients with type 2 diabetes are at a particular high risk for cardiovascular disease [4], protective cardiovascular effects of GLP-1 based therapies might hold great potential to limit cardiovascular risk in this population [2], [5]. Beneficial cardiovascular effects of GLP-1 based therapies are currently emerging [2]. Specifically, we and others have demonstrated DPP-IV inhibition to reduce plaque inflammation and increase plaque collagen content in apoe−/− mice [6], [7], [8], [9]. However, as DPP-IV has various substrates and thus degrades a large magnitude of peptides [10], [11], it currently remains unknown to what extent these anti-inflammatory, plaque stabilizing effects can be attributed to GLP-1. Furthermore, not only GLP-1 but also its split products – whose creation get modulated by DPP-4 inhibition – might have cardiovascular actions [5]. The GLP-1 metabolite (9-37) which does not activate the GLP-1 receptor, was thereby found to have similar cardioprotective effects as GLP-1 in context of acute myocardial infarction [12], [13]. These actions were preserved in the absence of the GLP-1 receptor suggesting the presence of an additional yet not identified receptor system [12]. Beneficial metabolic effects – including a reduction of body weight and improved insulin sensitivity have further been described for the c-terminal GLP-1 split product (28-37) [14], [15]. Clear specification of cardiovascular actions of these split products under in vivo conditions are currently lacking. We therefore studied the vascular effects of GLP-1(7-37) and its split products GLP-1(9-37) and GLP-1(28-37) on plaque phenotype with a particular emphasis on features of plaque morphology and stability in apoe−/− mice as a mouse model of atherosclerosis.
Section snippets
Construction of recombinant adeno-associated viral constructs
Vectors carried transgene cassettes encoding β-galactosidase (LacZ) as control, GLP-1(7-37), GLP-1(9-37) or GLP-1(28-37) under control of a cytomegalovirus (CMV) promoter. The pseudotyping strategy was used to produce AAV vectors encapsidated in an AAV8 capsid (AAV2.8) as previously reported [16]. Cloning was inspected by sequencing and restriction digests. Vectors were purified by standard caesium sedimentation. Titers were determined via TaqMan RealTime polymerase chain reaction (PCR) as
Animal data and metabolic profile
Using an adenovirus associated vector system (AAV) overexpression of GLP-1(7-37), GLP-1(9-37) and GLP-1(28-37) resulted in a significant elevation of serum peptide levels at day 21 after injection (Table 1). There was no change in body weight or circulating MCP-1 levels with either molecular form of GLP-1 (Table 1). Overexpressing GLP-1(7-37) but not GLP-1(9-37) or GLP-1(28-37) resulted in improved glucose tolerance (Fig. 1).
Atherosclerotic lesion extension
In order to investigate the effect of GLP-1 isoforms on lesion extent,
Discussion
The present study demonstrates GLP-1(7-37) in addition to GLP-1(9-37) and GLP-1(28-37) to similarly reduce plaque macrophage infiltration and MMP-9 expression, increase plaque collagen content as well as fibrous cap thickness while not significantly effecting atherosclerotic lesion size. Thus, our data suggests GLP-1 and its split products to reduce plaque vulnerability in this mouse model of vascular disease. As plaque erosion and rupture are major causes for myocardial infarction and vascular
Disclosures
ML served as a speaker for Novo Nordisk, Merck Sharp and Dohme, Boehringer Ingelheim, Bristol-Myers Squibb, Sanofi Aventis and Roche and is advisor to Astra Zeneca. All authors declare no duality of interest associated with this manuscript.
MB and AL: experimental and study design, experimental conduction, data interpretation, drafting of the manuscript, JM and CL: virus production, help with experimental conduction, drafting of the manuscript, FK and SR: help with experimental conduction,
Acknowledgement
This study is supported by grants from the German Heart Foundation/German Foundation of Heart Research and the Ernst and Berta Grimmke Stiftung to M.B., the German scientific foundation (DFG) to ML.
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MB and AL contributed equally to this work.