Crosstalk Between Oxidative Stress and Endoplasmic Reticulum (ER) Stress in Endothelial Dysfunction and Aberrant Angiogenesis Associated With Diabetes: A Focus on the Protective Roles of Heme Oxygenase (HO)-1.

Hatem Maamoun,Tarek Benameur,Shankar Munusamy,Gianfranco Pintus,Abdelali Agouni

doi:10.3389/fphys.2019.00070

Abstract

Type-2 diabetes prevalence is continuing to rise worldwide due to physical inactivity and obesity epidemic. Diabetes and fluctuations of blood sugar are related to multiple micro- and macrovascular complications, that are attributed to oxidative stress, endoplasmic reticulum (ER) activation and inflammatory processes, which lead to endothelial dysfunction characterized, among other features, by reduced availability of nitric oxide (NO) and aberrant angiogenic capacity. Several enzymatic anti-oxidant and anti-inflammatory agents have been found to play protective roles against oxidative stress and its downstream signaling pathways. Of particular interest, heme oxygenase (HO) isoforms, specifically HO-1, have attracted much attention as major cytoprotective players in conditions associated with inflammation and oxidative stress. HO operates as a key rate-limiting enzyme in the process of degradation of the iron-containing molecule, heme, yielding the following byproducts: carbon monoxide (CO), iron, and biliverdin. Because HO-1 induction was linked to pro-oxidant states, it has been regarded as a marker of oxidative stress; however, accumulating evidence has established multiple cytoprotective roles of the enzyme in metabolic and cardiovascular disorders. The cytoprotective effects of HO-1 depend on several cellular mechanisms including the generation of bilirubin, an anti-oxidant molecule, from the degradation of heme; the induction of ferritin, a strong chelator of free iron; and the release of CO, that displays multiple anti-inflammatory and anti-apoptotic actions. The current review article describes the major molecular mechanisms contributing to endothelial dysfunction and altered angiogenesis in diabetes with a special focus on the interplay between oxidative stress and ER stress response. The review summarizes the key cytoprotective roles of HO-1 against hyperglycemia-induced endothelial dysfunction and aberrant angiogenesis and discusses the major underlying cellular mechanisms associated with its protective effects.

Highlights

Endothelial dysfunction is considered as the structural alteration and functional impairment of vascular endothelial layer, characterized by a reduction in NO bioavailability and aberrant angiogenesis (Lerman and Burnett, 1992; Creager et al, 2003; Jamwal and Sharma, 2018)
We have reviewed the major mechanisms contributing to endothelial dysfunction, the key initial step in the onset of atherosclerotic process, in the context of diabetes and hyperglycemia
We have reviewed the cytoprotective roles of Heme oxygenase (HO)-1 against diabetes- and hyperglycemia-induced endothelial dysfunction and aberrant angiogenesis and discussed the major underlying molecular mechanisms associated with these protective effects with special emphasis on signaling pathways related to oxidative stress and endoplasmic reticulum (ER) stress response

Summary

Introduction

Endothelial dysfunction is considered as the structural alteration and functional impairment of vascular endothelial layer, characterized by a reduction in NO bioavailability and aberrant angiogenesis (Lerman and Burnett, 1992; Creager et al, 2003; Jamwal and Sharma, 2018). We have reviewed the cytoprotective roles of HO-1 against diabetes- and hyperglycemia-induced endothelial dysfunction and aberrant angiogenesis and discussed the major underlying molecular mechanisms associated with these protective effects with special emphasis on signaling pathways related to oxidative stress and ER stress response.

Results

Conclusion