Activation of heme oxygenase-1 by Ginkgo biloba extract differentially modulates endothelial and smooth muscle-like progenitor cells for vascular repair

Abstract

Vascular progenitors such as endothelial progenitor cells (EPCs) and smooth muscle-like progenitor cells (SMPCs) may play different roles in vascular repair. Ginkgo biloba extract (GBE) is an exogenous activator of heme oxygenase (HO)-1, which has been suggested to improve vascular repair; however, the detailed mechanisms have yet to be elucidated. This study aimed to investigate whether GBE can modulate different vascular progenitor cells by activating HO-1 for vascular repair. A bone marrow transplantation mouse model was used to evaluate the in vivo effects of GBE treatment on wire-injury induced neointimal hyperplasia, which is representative of impaired vascular repair. On day 14 of GBE treatment, the mice were subjected to wire injury of the femoral artery to identify vascular reendothelialization. Compared to the mice without treatment, neointimal hyperplasia was reduced in the mice that received GBE treatment for 28 days in a dose-dependent manner. Furthermore, GBE treatment increased bone marrow-derived EPCs, accelerated endothelial recovery, and reduced the number of SMPCs attached to vascular injury sites. The effects of GBE treatment on neointimal hyperplasia could be abolished by co-treatment with zinc protoporphyrin IX, an HO-1 inhibitor, suggesting the in vivo role of HO-1. In this in vitro study, treatment with GBE activated human early and late EPCs and suppressed SMPC migration. These effects were abolished by HO-1 siRNA and an HO-1 inhibitor. Furthermore, GBE induced the expression of HO-1 by activating PI3K/Akt/eNOS signaling in human late EPCs and via p38 pathways in SMPCs, suggesting that GBE can induce HO-1 in vitro through different molecular mechanisms in different vascular progenitor cells. Accordingly, GBE could activate early and late EPCs, suppress the migration of SMPCs, and improve in vivo vascular repair after mechanical injury by activating HO-1, suggesting the potential role of pharmacological HO-1 activators, such as GBE, for vascular protection in atherosclerotic diseases.

Targeting the redox system for cardiovascular regeneration in aging

“…et al, 2003). Furthermore, the natural Ginkgo biloba extract activates EPCs, suppresses the migration of smooth muscle-like progenitor cells (SMPCs), and enhances vascular protection in atherosclerosis (Wu et al, 2019).…”

“…It was also previously discovered, in a rabbit model of balloon‐damaged arteries, that Probucol can stimulate the regeneration of functional ECs and inhibit intimal thickening by activating NO‐cGMP pathway (Lau et al., 2003 ). Furthermore, the natural Ginkgo biloba extract activates EPCs, suppresses the migration of smooth muscle‐like progenitor cells (SMPCs), and enhances vascular protection in atherosclerosis (Wu et al., 2019 ).…”

Melatonin Improves Ischemia-Induced Circulation Recovery Impairment in Mice with Streptozotocin-Induced Diabetes by Improving the Endothelial Progenitor Cells Functioning

“…In the present study, melatonin protected EPCs from the HG environment via the upregulation of AMPK, eNOS, and HO-1 expression and reduction of ROS. We have explored some critical pathways involved in the enhancement of EPC function under HG conditions via AMPK, eNOS, and HO-1 [ 26 , 27 , 28 ]. AMPK appears to activate eNOS, given that AMPK activators promote eNOS phosphorylation on Ser1177 [ 29 , 30 ].…”

Roles of Reactive Oxygen Species in Vascular Complications of Diabetes: Therapeutic Properties of Medicinal Plants and Food

“…Ginkgolide B, a natural product from Ginkgo biloba L., targeted NOX-4, LOX-1, MCP-1, ICAM-1, and VCAM-1 to abrogate ox-LDL-induced oxidative damage in HUVECs [156,157]. As an HO-1 activator, Ginkgo biloba extract improved vascular repairment by activating PI3K/Akt/eNOS signaling in endothelial progenitor cells [158].…”