High glucose/High Lipids impair vascular adiponectin function via inhibition of caveolin-1/AdipoR1 signalsome formation

Abstract

Reduced levels of adiponectin (APN) contribute to cardiovascular injury in the diabetic population. Recent studies demonstrate elevated circulating APN levels are associated with endothelial dysfunction during pre-diabetes, suggesting the development of APN resistance. However, mechanisms leading to, and the role of, vascular APN resistance in endothelial dysfunction remain unidentified. The current study determined whether diabetes cause endothelial APN resistance, and by what mechanisms. Under high glucose/high lipids (HG/HL), APN-stimulated nitric oxide production by HUVEC was decreased, phosphorylation of eNOS, AMPK, and Akt was attenuated (P<0.01), and APN’s anti-TNFα effect was blunted (P<0.01). APN receptor expression remained normal, whereas Cav1 expression was reduced in HG/HL cells (P<0.01). The AdipoR1/Cav1 signaling complex was dissociated in HG/HL cells. Knock-down of Cav1 inhibited APN’s anti-oxidative and anti-inflammatory actions. Conversely, preventing HG/HL-induced Cav1 downregulation by Cav1 overexpression preserved APN signaling in HG/HL cells. Knock-in of a wild type Cav1 in Cav1 knock-down cells restored caveolae structure and rescued APN signaling. In contrast, knock-in of a mutated Cav1 scaffolding domain restored caveolae structure, but failed to rescue APN signaling in Cav1 knock-down cells. Finally, AdipoR1/Cav1 interaction was significantly reduced in diabetic vascular tissue, and the vasorelaxative response to APN was impaired in diabetic animals. The current study demonstrates for the first time the interaction between AdipoR1 and Cav1 is critical for adiponectin-mediated vascular signaling. The AdipoR1/Cav1 interaction is adversely affected by HG/HL, due largely to reduced Cav1 expression, supporting a potential mechanism for the development of APN resistance, contributing to diabetic endothelial dysfunction.

Adiponectin at Physiologically Relevant Concentrations Enhances the Vasorelaxative Effect of Acetylcholine via Cav-1/AdipoR-1 Signaling

“…The caveolins, scaffolding proteins within the caveolae, compartmentalize and concentrate signaling molecules, and are responsible for endothelial function regulation [ 15 , 16 ]. We have recently demonstrated the existence of a membrane-situated APN signalsome, containing APN receptor 1 (AdipoR1) and caveolin-1 (Cav-1), that facilitates APN signaling transduction [ 17 ]. Our study demonstrated direct interaction between AdiopR1 and Cav-1 (the primary caveolin subtype in HUVECs) [ 17 ].…”

“…We have recently demonstrated the existence of a membrane-situated APN signalsome, containing APN receptor 1 (AdipoR1) and caveolin-1 (Cav-1), that facilitates APN signaling transduction [ 17 ]. Our study demonstrated direct interaction between AdiopR1 and Cav-1 (the primary caveolin subtype in HUVECs) [ 17 ].…”

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

“…For experiments, cells from passages 4-6 were grown to 90% confluence and were then cultured in ECM (FBS-free) for 24 h. Then, HMECs were randomly selected to receive one of the following treatments: normal glucose/normal lipid culture for 24 h (Control, FBS-free); or HG (33.3 mM D-glucose)/HL (250 µM palmitate) [12] culture for 24 h after GLP-1 (1, 10, 100, or 1000 nM) or ghrelin (1, 10, 100, or 1000 nM) treatment for 30 min. In some experiments, HMECs were pre-treated with the Akt inhibitor MK2206 (10 µM), the p38 inhibitor SB203580 (10 µM), the ERK1/2 inhibitor SCH772984 (10 µM), or the JNK1/2 inhibitor SP600125 (20 µM) for 30 min and then subjected to the HG/HL protocol.…”

Role of Adipokines in Cardiovascular Disease

“…Treatment with high glucose/high lipid disrupts the AdipoR1/Cav signalosome, leading to APN resistance. 85 The diabetic condition itself may cause cardiac APN resistance, diminishing the cardioprotective effects of APN. High glucose/high lipid treatments impair APN activation of AMPK-dependent ACC (Acetyl-CoA Carboxylase) signaling, as well as AMPK-independent antioxidative/ antinitrative protection, severely inhibiting the cardiopro-TNF-α-induced expression of intracellular adhesion molecule-1 and VCAM-1 in cultured endothelial cells.…”