Endothelial GLP-1 (Glucagon-Like Peptide-1) Receptor Mediates Cardiovascular Protection by Liraglutide In Mice With Experimental Arterial Hypertension.

Abstract

OBJECTIVE:

Cardiovascular outcome trials demonstrated that GLP-1 (glucagon-like peptide-1) analogs including liraglutide reduce the risk of cardiovascular events in type 2 diabetes mellitus. Whether GLP-1 analogs reduce the risk for atherosclerosis independent of glycemic control is challenging to elucidate as the GLP-1R (GLP-1 receptor) is expressed on different cell types, including endothelial and immune cells. Approach and Results: Here, we reveal the cardio- and vasoprotective mechanism of the GLP-1 analog liraglutide at the cellular level in a murine, nondiabetic model of arterial hypertension. Wild-type (C57BL/6J), global (Glp1r-/-), as well as endothelial (Glp1rflox/floxxCdh5cre) and myeloid cell-specific knockout mice (Glp1rflox/floxxLysMcre) of the GLP-1R were studied, and arterial hypertension was induced by angiotensin II. Liraglutide treatment normalized blood pressure, cardiac hypertrophy, vascular fibrosis, endothelial dysfunction, oxidative stress, and vascular inflammation in a GLP-1R-dependent manner. Mechanistically, liraglutide reduced leukocyte rolling on the endothelium and infiltration of myeloid Ly6G-Ly6C+ and Ly6G+Ly6C+ cells into the vascular wall. As a consequence, liraglutide prevented vascular oxidative stress, reduced S-glutathionylation as a marker of eNOS (endothelial NO synthase) uncoupling, and increased NO bioavailability. Importantly, all of these beneficial cardiovascular effects of liraglutide persisted in myeloid cell GLP-1R-deficient (Glp1rflox/floxxLysMcre) mice but were abolished in global (Glp1r-/-) and endothelial cell-specific (Glp1rflox/floxxCdh5cre) GLP-1R knockout mice.

CONCLUSIONS:

GLP-1R activation attenuates cardiovascular complications of arterial hypertension by reduction of vascular inflammation through selective actions requiring the endothelial but not the myeloid cell GLP-1R.

• Authors: Johanna Helmstädter, Katie Frenis, Konstantina Filippou, Alexandra Grill, Mobin Dib, Sanela Kalinovic, Franziska Pawelke, Kamil Kus, Swenja Kröller-Schön, Matthias Oelze, Stefan Chlopicki, Detlef Schuppan, Philip Wenzel, Wolfram Ruf, Daniel J Drucker, Thomas Münzel, Andreas Daiber, Sebastian Steven
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 40 Issue 1 Pg. 145-158 (01 2020) ISSN: 1524-4636 [Electronic] United States
• PMID: 31747801 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glucagon-Like Peptide-1 Receptor
• Hypoglycemic Agents
• RNA
• Liraglutide

Topics

• Animals
• Atherosclerosis (etiology, genetics, prevention & control)
• Blood Pressure (drug effects)
• Blotting, Western
• Cells, Cultured
• Disease Models, Animal
• Endothelial Cells (metabolism, pathology)
• Glucagon-Like Peptide-1 Receptor (biosynthesis, genetics)
• Hypertension (complications, genetics, metabolism)
• Hypoglycemic Agents (pharmacology)
• Liraglutide (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• RNA (genetics)