Heat Shock Protein 70 Mediates the Protective Effect of Naringenin on High-Glucose-Induced Alterations of Endothelial Function

Abstract

Endothelial dysfunction plays a pivotal role in the development and progression of diabetic vascular complications. Naringenin (Nar) is a flavanone bioactive isolated from citrus fruits known to have in vitro and in vivo antidiabetic properties. However, whether Nar affects endothelial function remains unclear in diabetes or under high-glucose (HG) condition. Using an in vitro model of hyperglycemia in human umbilical vein endothelial cells (HUVECs), we found that Nar administration markedly attenuated HG-induced alterations of endothelial function, evidenced by the mitigation of oxidative stress and inflammation, the reduction of cell adhesion molecular expressions, and the improvement of insulin resistance. We also found that HG exposure significantly reduced the levels of intracellular heat shock protein 70 (iHSP70 or iHSPA1A) and the release of HSP70 from HUVECs. HSP70 depletion mimicked and clearly diminished the protective effects of Nar on HG-induced alterations of endothelial function. In addition, Nar treatment significantly enhanced iHSP70 protein levels through a transcription-dependent manner. These results demonstrated that Nar could protect HUVECs against HG-induced alterations of endothelial function through upregulating iHSP70 protein levels. These findings are also helpful in providing new therapeutic strategies that are promising in the clinical use of Nar for the treatment of diabetes and diabetic complications.

Atheroprotective Aspects of Heat Shock Proteins

“…Thus, low levels of HSP70 in patients with progressive atherosclerosis may manifest as a result of primary endothelial dysfunction. At the same time, HSP70 does not induce NO production by macrophages, and is similarly capable of inducing NO production by endothelial cells [65].…”

Research Progress of Flavonoids Regulating Endothelial Function

“…Li et al [ 74 ] confirmed that naringenin could activate AMPKα/Sirt1 signaling pathway, restore mitochondrial Ca2+ balance, reduce eNOS uncoupling, and increase NO bioavailability to improve damaged ECs by new transcriptomics technology. Its up-regulation of heat-shock protein 70 in endothelial cells has potential implications for the amelioration of endothelial damage in diabetes and related diseases [ 133 ]. Naringenin attenuates high-glucose-induced apoptosis in HUVECs, which may play a role in increasing HO-1 expression in HUVECs through up-regulation of PI3K/Akt or JNK pathways [ 75 ].…”