2-Hydroxyl hispolon reverses high glucose-induced endothelial progenitor cell dysfunction through the PI3K/Akt/eNOS...

Area of Science:

• Biomedical Science
• Endocrinology
• Vascular Biology

Background:

• Diabetes mellitus (DM) causes hyperglycemia, leading to increased reactive oxygen species (ROS) and endothelial progenitor cell (EPC) dysfunction.
• EPC dysfunction impairs angiogenesis and contributes to complications like critical limb ischemia (CLI).

Purpose of the Study:

• To investigate the therapeutic potential of 2-hydroxy hispolon (2HH), a hispolon derivative, in reversing high glucose-induced EPC dysfunction.
• To evaluate 2HH's effects on angiogenesis and cell signaling pathways in diabetic models.

Main Methods:

• In vitro studies assessed 2HH's impact on outgrowth endothelial cells (OECs), circulating angiogenic cells (CACs), and endothelial cells (ECs) under high-glucose conditions.
• In vivo studies utilized a high-fat diet and streptozotocin-induced diabetic mouse model with hindlimb ischemia to evaluate 2HH's effects on angiogenesis and CAC mobilization.

Main Results:

• 2HH treatment significantly improved EPC proliferation, migration, tube formation, nitric oxide (NO) synthesis, and reduced ROS under high-glucose conditions.
• 2HH activated the AMP-activated protein kinase (AMPK)/haem oxygenase-1 (HO-1) and phosphoinositide 3-kinase (PI3K)/Akt/endothelial NOS (eNOS) signaling pathways in EPCs.
• In vivo, 2HH enhanced blood flow recovery, improved limb salvage, increased circulating CACs, and boosted capillary density in ischemic hindlimbs of diabetic mice.

Conclusions:

• 2HH effectively mitigates high glucose-induced oxidative stress and NO deficiency, thereby preventing EPC dysfunction.
• The therapeutic effects of 2HH are mediated through the activation of PI3K/Akt/eNOS and AMPK/HO-1 signaling pathways.
• 2HH presents a promising therapeutic strategy for preventing critical limb ischemia in patients with diabetes.