GLP-1 and Ghrelin Attenuate High Glucose/High Lipid-Induced Apoptosis and Senescence of Human Microvascular Endothelial Cells

Abstract

Background/Aims: GLP-1 and ghrelin are common appetite-regulating hormones. Both have multiple functions beyond metabolic regulation. However, the effects of GLP-1 and ghrelin on endothelial biology are not fully understood. Here, we investigate the roles of GLP-1 and ghrelin in microvascular endothelial apoptosis and senescence. Methods: Human microvascular endothelial cells (HMECs) were exposed to high glucose/high lipid (HG/HL) conditions and treated with GLP-1 or ghrelin. Cellular apoptosis, senescence, and mitochondrial function were measured. In addition, the MAPK and Akt signaling pathways were examined. Results: Both GLP-1 and ghrelin treatment decreased the number of TUNEL-positive cells and inhibited caspase-3 and PARP cleavage and mitochondrial dysfunction in HG/HL-exposed HMECs. GLP-1, but not ghrelin decreased the number of β-galactosidase (β-gal)-positive cells. Furthermore, GLP-1 and ghrelin inhibited ERK1/2, JNK1/2, and p38 signaling. GLP-1 suppressed Akt signaling, but ghrelin had no effect. Moreover, JNK1/2 and p38 inhibitors, but not ERK1/2 and Akt inhibitors, decreased the number of TUNEL-positive cells. Additionally, only the Akt inhibitor decreased the number of β-gal-positive cells. Conclusion: These results demonstrate that GLP-1 and ghrelin inhibit mitochondrial dysfunction under HG/HL conditions, and suppress endothelial apoptosis via inhibiting JNK1/2 and p38 signaling; moreover, GLP-1 alleviates endothelial senescence via inactivating Akt signaling.

Pretreatment of ghrelin protects H9c2 cells against hypoxia/reoxygenation-induced cell death via PI3K/AKT and AMPK pathways

“…Ghrelin is also implicated in protecting vascular endothelial cells and preventing various stimulus-induced apoptosis. Liao et al reported that ghrelin attenuated high glucose and lipid-induced apoptosis and senescence of human microvascular endothelial cells [16]. Besides, ghrelin may act as a survival factor in cardiomyocytes H9c2 through inhibiting apoptosis and oxidative stress [17,18].…”

Sulodexide Slows Down the Senescence of Aortic Endothelial Cells Exposed to Serum from Patients with Peripheral Artery Diseases

“…Senescence of the endothelial cells is not only due to shortening of their telomeres but may also be induced by such factors as high glucose, Angiotensin II or oxidative stress [6, 7, 8]. These factors play an important role in various types of pathologies of the cardiovascular system in humans.…”

Glucagon-Like Peptide-1 Modulates Cholesterol Homeostasis by Suppressing the miR-19b-Induced Downregulation of ABCA1

“…The toxicity of cholesterol enriches the connotation of lipotoxicity, which contributes to the development of T2DM [37,38]. GLP-1 as a promising anti-diabetic drug, could improve lipid accumulation and inflammation in hepatocytes [19,20,39]. However, the mechanism of this effect is poorly understood.…”

“…Because of the key role played by GLP-1 in mediating lipid metabolism, much researches has aimed to understand the cellular and molecular mechanisms involved [18,19,40]. Fat accumulation in the liver is regarded as a key pathogenic factor of metabolic diseases.…”

“…GLP-1 has unique abilities to modulate lipid metabolism by affecting lipid assimilation and transport, fat formation and decomposition, hepatic lipid metabolism and reverse cholesterol transport [17,18,19]. The apolipoprotein A-I gene, encoding the primary anti-atherogenic factor in high-density lipoprotein (HDL) particles, is increased in both GLP-1 and exendin-4-treated HepG2 cells, and this phenomenon is accompanied by similar changes in the expression of ABCA1 [20].…”