Maamoun Hatem, Benameur Tarek, Pintus Gianfranco, Munusamy Shankar, Agouni Abdelali
Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
College of Medicine, King Faisal University, Al-Ahsa, Saudi Arabia.
Front Physiol. 2019 Feb 11;10:70. doi: 10.3389/fphys.2019.00070. eCollection 2019.
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.
由于缺乏身体活动和肥胖流行，2型糖尿病在全球的患病率持续上升。糖尿病和血糖波动与多种微血管和大血管并发症相关，这些并发症归因于氧化应激、内质网（ER）激活和炎症过程，这些过程导致内皮功能障碍，其特征包括一氧化氮（NO）可用性降低和异常血管生成能力等。已发现几种酶促抗氧化剂和抗炎剂对氧化应激及其下游信号通路具有保护作用。特别值得关注的是，血红素加氧酶（HO）同工型，特别是HO-1，作为炎症和氧化应激相关疾病中的主要细胞保护因子，已引起了广泛关注。HO在含铁分子血红素的降解过程中作为关键的限速酶发挥作用，产生以下副产物：一氧化碳（CO）、铁和胆绿素。由于HO-1的诱导与促氧化状态有关，它一直被视为氧化应激的标志物；然而，越来越多的证据表明该酶在代谢和心血管疾病中具有多种细胞保护作用。HO-1的细胞保护作用取决于多种细胞机制，包括从血红素降解中产生抗氧化分子胆红素；诱导铁蛋白，一种强大的游离铁螯合剂；以及释放CO，CO具有多种抗炎和抗凋亡作用。本综述文章描述了导致糖尿病内皮功能障碍和血管生成改变的主要分子机制，特别关注氧化应激和内质网应激反应之间的相互作用。综述总结了HO-1对高血糖诱导的内皮功能障碍和异常血管生成的关键细胞保护作用，并讨论了与其保护作用相关的主要潜在细胞机制。
