GLP-1 secretion and signaling in patients with aneurysmal enlargement of the thoracic aorta : a potential contributor to reduced prevalence of aneurysm in diabetes

An aortic aneurysm is a localized dilation of the artery, greater than 50% of the normal size. It is the result of a weakening of the aortic wall, and untreated or unrecognized aortic aneurysms may be fatal due to massive internal bleeding, as a result of dissection or rupture of the aneurysm. The aorta is divided into two major sections; the thoracic and the abdominal aorta. Approximately 25% of all aneurysms are Thoracic aortic aneurysms (TAA) and the remaining are Abdominal aortic aneurysms (AAA). Most commonly, TAAs are located in the ascending aorta (AscAA). There are different conditions that involve increased risk of TAA formation, for example, bicuspid aortic valve (BAV), a congenital condition where the aortic valve has two instead of three (tricuspid aortic valve (TAV)) cusps. The mechanisms underlying the increased prevalence of TAA among BAV patients are largely unknown. However, differential mechanisms have been indicated in aneurysm formation in BAV and TAV patients. Interestingly though, the prevalence of AAA and TAA among BAV and TAV patients alike is reduced among those with type 2 diabetes (T2D). The reduced prevalence of TAA in T2D has been speculated to involve pharmacological treatment.

The peptide hormone, Glucagon-like peptide-1 (GLP-1) is an intestinal hormone and neuronal peptide with an important role in glucose metabolism, primarily through enhanced glucose-induced insulin secretion, wherefore GLP-1 also forms the basis of current anti-diabetic therapy. Although studies have indicated defective postprandial secretion of GLP-1, T2D is also associated with increased fasting plasma levels of GLP-1. Of note, the GLP-1 receptor is expressed in various different tissues including the vasculature, and GLP-1-based therapy prevents aneurysm formation in vivo. Furthermore, clinical studies indicate that GLP-1 governs many of the mechanisms implicated in TAA formation/progression, such as inflammation, oxidative stress, and proteolytic activity. Smooth muscle cells (SMCs) play a central role in TAA pathology, where the transition from a differentiated (with contractile function) to a de-differentiated (synthetic) phenotype is important in the formation/progression of TAA. Some of the indicated beneficial effects of GLP-1-based therapy on TAA pathology may be speculated to involve the proteoglycan, syndecan-1 (Sdc-1), whose expression is regulated by intracellular targets of the GLP-1 receptor (GLP-1R). Sdc-1 modulates pro-inflammatory processes and has a protective role in aortic aneurysm. Nevertheless, it is not known whether T2D or enhanced fasting plasma GLP-1 in T2D is associated with altered inflammatory profile, proteolytic activity, or Sdc-1 expression, nor are the effects of GLP-1R activation on SMCs in the presence/absence of diabetic conditions well characterized.

Our hypothesis was that elevated fasting plasma GLP-1 levels, in T2D patients with valve disease, may contribute to the reduced risk of AscAA in T2D patients. The aim of this project was to further understanding of a potential role for GLP-1 in the reduced prevalence of AscAA in T2D, by assessing potential correlations between elevated fasting plasma GLP-1 and processes involved in aortic aneurysm formation, including inflammation, proteolytic activity, and Sdc-1 expression. In addition, we aimed to determine potential direct effects of GLP-1 signaling on aortic SMCs. In Paper I, we show that patients with T2D are characterized by a shift towards an anti-inflammatory profile, which is associated with elevated fasting plasma GLP-1. Furthermore, a potential role for this anti-inflammatory shift in the reduced prevalence of AscAA in T2D patients is indicated by the inflammatory Th1 bias of immune responses in patients with AscAA. In Paper II, the results show elevated expression of Sdc-1 in the aorta of T2D patients, facilitating a possible role for this increase in T2D- associated reduced prevalence of AscAA. We also demonstrate increased Sdc-1 expression in AscAA patients in association with increased infiltration of macrophages, substantiating data from in vivo studies indicating a role for Sdc-1 upregulation on immune cells as a counterbalancing response to TAA formation. In Paper III, results do not indicate an association between T2D and increased Sdc-1 expression in aortic adventitial tissue among BAV patients. Nor was increased macrophage infiltration or Sdc-1 expression detected in association with AscAA among BAV patients. Finally, in Paper IV, we show that GLP-1R is highly expressed in differentiated aortic SMCs, as compared to de-differentiated SMCs, and its activation attenuates Angiotensin II induced downregulation of Sdc-1 expression. In addition, a diabetic milieu increased the gene expression of the differentiation markers (calponin and myosin). In conclusion, this study indicates that T2D is associated with a Th2 bias, and increased aortic expression of Sdc-1, which may play a role in the reduced prevalence of AscAA in T2D.

List of scientific papers

I. Stelia Ntika, Harshitha Jois, Karin Lång, Christian Olsson, Anders Franco-Cereceda, Hanna M. Björck and Camilla Krizhanovskii. Elevated glucagon-like peptide-1 and a Th2 shift may support reduced prevalence of thoracic aortic aneurysm in patients with diabetes. J Cardiovasc Dev Dis. 2021, 8, 143.
https://doi.org/10.3390/jcdd8110143

II. Stelia Ntika, Linda M Tracy, Anders Franco-Cereceda, Hanna M Björck, Camilla Krizhanovskii. Syndecan-1 Expression Is Increased in the Aortic Wall of Patients with Type 2 Diabetes but Is Unrelated to Elevated Fasting Plasma Glucagon-Like Peptide-1. Biomedicines. 2021, 9, 697.
https://doi.org/10.3390/biomedicines9060697

III. Stelia Ntika, Linda M. Tracy, Anders Franco-Cereceda, Hanna M. Björck and Camilla Krizhanovskii. Type 2 Diabetes is not associated with elevated levels of Syndecan-1 in adventitia among patients with bicuspid aortic valve. [Manuscript]

IV. Stelia Ntika, Linda M. Tracy, Anders Franco-Cereceda, Hanna M. Björck and Camilla Krizhanovskii. Glucagon-like peptide-1 receptor activation counteracts Angiotensin II induced reduction of Syndecan-1 expression in aortic smooth muscle cells. [Manuscript]