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

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.

Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases

“…Frontiers in Neuroscience | www.frontiersin.org and biliverdin (Rochette et al, 2018;Maamoun et al, 2019). In murine models of doxorubicin (DOX) and ischemia/reperfusion (I/R)-induced cardiomyopathy, administering DOX to mice induced cardiomyopathy with a rapid, systemic accumulation of non-heme iron via heme degradation by Nrf2-mediated upregulation of HO-1, which effect was abolished in Nrf2deficient mice (Fang et al, 2019).…”

Antioxidant Defence Systems and Oxidative Stress in Poultry Biology: An Update

“…Heme Oxygenase-1, a 32 kDa protein, known as heat shock protein-32 (HSP32), is responsible for the degradation of haem with the formation of carbon monoxide (CO), biliverdin and free iron. Similar to HSP70, HO-1 is the stress-inducible isoform of the three HO isoforms described to date, providing a critical protective mechanism in avian systems responsible for adaptation to oxidative, inflammatory and cytotoxic stress [136,137]. In most tissues HO-1 is expressed at a relatively low house-keeping level and it can be induced by various oxidative stress-related insults including haem, ultraviolet light, heavy metals, cytokines, hydrogen peroxide, nitric oxide (NO) and glutathione depletion [138,139].…”

A miR-494 dependent feedback loop regulates ER stress

“…We previously showed that miR-494 is responsive to radiation and chemical inducers of genotoxic stress and functions to increase endothelial senescence during DNA damage responses (24). Given the intricate relationship between radiation, oxidative stress and ER stress (14,17), we asked if ER stress affected miR-494 expression and function. First, we confirmed a robust ER stress response to known inducers, tunicamycin (TCN) and thapsigargin (TG), in human umbilical vein endothelial cells (HUVECs) by measuring the level of the transcription factors spliced XBP1 (mRNA: sXBP1, protein: XBP1s) and DDIT3 (CHOP), which are well characterized markers of the ER stress response ( Fig.…”

“…Furthermore, ER stress has been shown to contribute to vascular dysfunction and cardiac damage in preclinical models of hypertension (11). Similarly, oxidative stress and ER stress pathways have been shown to be interlinked in ECs in metabolic syndromes such as diabetes and non-alcoholic fatty liver disease (NAFLD) (12)(13)(14)(15)(16). Therefore, ECs have adopted several mechanisms to regulate cell fate decisions in response to both acute and chronic ER stress (17).…”