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 ( Glp1r f lox/floxxCdh5 cre ) and myeloid cell–specific knockout mice ( Glp1r flox/flox xLysM cre ) 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 ( Glp1r flox/flox xLysM cre ) mice but were abolished in global ( Glp1r −/− ) and endothelial cell–specific ( Glp1r flox/flox xCdh5 cre ) 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.

Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain

“…At other body sites (e.g. the myocardium), GLP-1R agonist treatment has been reported to improve endothelial function, energy metabolism, and exert immunomodulatory effects 35 – 39 , 63 , 64 . We thus postulated that GLP-1R agonists might have neurovascular protective effects that partly explains its general applicability as potential therapeutics for multiple neurodegenerative conditions with ageing-associated neurovascular defects as a shared pathological component.…”

“…myocardial infarction, stroke) in diabetic patients 34 , while animal tests revealed vascular protective and immunomodulatory effects in peripheral organs 35 – 39 . In the brain, GLP-1R is expressed by multiple cell types including microglia and subsets of neurons 28 , 40 , 41 , while peripherally it has been reported to be expressed by subsets of vascular and immune cells 38 , 39 . It remains to be tested whether GLP-1R agonists may act partly via reversal of neurovascular ageing, accounting for the general applicability as potential therapeutics for multiple neurodegenerative conditions.…”

Pathological Roles of Mitochondrial Oxidative Stress and Mitochondrial Dynamics in Cardiac Microvascular Ischemia/Reperfusion Injury

“…In order to attenuate oxidative stress in endothelial cells under I/R injury, several drugs or approaches have been developed. Ginkgolide A (GA) [104] and liraglutide [105] have anti-oxidative properties and could reduce endothelial oxidative stress, attenuating microvascular damage induced by reperfusion. Peroxisome proliferator-activated receptor γ (PPAR-γ) agonist inhibits vascular complications in I/R injury through modulation of oxidative stress and endoplasmic reticulum stress [106].…”

GLP-1 Receptor Agonists in Diabetic Kidney Disease: From Clinical Outcomes to Mechanisms

“…DKD is associated with endothelial dysfunction (Chen et al, 2020). Endothelial GLP-1R has been shown to be involved in endothelial dysfunction in a mouse angiotensin II-induced hypertension model (Helmstadter et al, 2020). Liraglutide was found to increase eNOS phosphorylation and nitric oxide (NO) production via AMPK-dependent pathways in endothelial cells (Li et al, 2016;Honda et al, 2018;Han et al, 2019).…”