Hypoxic/Ischemic Inflammation, MicroRNAs and δ-Opioid Receptors: Hypoxia/Ischemia-Sensitive Versus-Insensitive Organs

Abstract

Hypoxia and ischemia cause inflammatory injury and critically participate in the pathogenesis of various diseases in various organs. However, the protective strategies against hypoxic and ischemic insults are very limited in clinical settings up to date. It is of utmost importance to improve our understanding of hypoxic/ischemic (H/I) inflammation and find novel therapies for better prevention/treatment of H/I injury. Recent studies provide strong evidence that the expression of microRNAs (miRNAs), which regulate gene expression and affect H/I inflammation through post-transcriptional mechanisms, are differentially altered in response to H/I stress, while δ-opioid receptors (DOR) play a protective role against H/I insults in different organs, including both H/I-sensitive organs (e.g., brain, kidney, and heart) and H/I-insensitive organs (e.g., liver and muscle). Indeed, many studies have demonstrated the crucial role of the DOR-mediated cyto-protection against H/I injury by several molecular pathways, including NLRP3 inflammasome modulated by miRNAs. In this review, we summarize our recent studies along with those of others worldwide, and compare the effects of DOR on H/I expression of miRNAs in H/I-sensitive and -insensitive organs. The alternation in miRNA expression profiles upon DOR activation and the potential impact on inflammatory injury in different organs under normoxic and hypoxic conditions are discussed at molecular and cellular levels. More in-depth investigations into this field may provide novel clues for new protective strategies against H/I inflammation in different types of organs.

Prediction of Early- and Late-Onset Pre-Eclampsia in the Preclinical Stage via Placenta-Specific Extracellular miRNA Profiling

“…It is known that hypoxia plays a different role in placentogenesis depending on gestational age: in the first trimester of pregnancy, it promotes trophoblast invasion and angiogenesis [58], but a prolonged hypoxic condition beyond the first trimester causes deficient trophoblast syncytialization, inadequate trophoblast invasion, and impaired vascular remodeling, resulting in placental dysfunction and pregnancy-induced hypertension such as pre-eclampsia/intrauterine growth restriction [59,60]. Some miRNAs are hypoxia-responsive molecules [61][62][63], and among which are placenta-specific miR-NAs, identified in the present study as being pre-eclampsia-associated markers. These include the following: mir-30e-5p, down-regulated under hypoxic conditions and causing apoptosis via the targeting of Bim [64]; decreased miR-320e, considered to be a marker of acute stroke in humans [65]; the miR-451a/MEF2D axis, affected by acidic conditions under hypoxia/ischemia, which controls cell proliferation, migration, and invasion via the Akt/GSK-3β signaling pathway [66]; the miR-451a/MIF axis, a key regulator of inflammatory processes under hypoxic conditions [67]; miR-22, induced due to myocardial ischemia-reperfusion injury and able to inhibit cardiomyocyte apoptosis via the targeting of the cAMP response element binding (CREB) protein, which regulates pro-apoptotic-related genes (Bax and p21) [68]; and miR-1307-3p, transcriptionally modulated by Hif-1α and promoting angiogenesis, cell proliferation, and invasion via the inhibition of DAB2IP and the activation of AKT/mTOR signaling [69].…”

Understanding human aging and the fundamental cell signaling link in age-related diseases: the middle-aging hypovascularity hypoxia hypothesis

“…Various aged-related chronic diseases, such as metabolic disorders, cardiovascular diseases, erectile dysfunction, cognition, and cancer, are associated with endocrine ( Asih et al, 2017 ; Diamanti-Kandarakis et al, 2017 ; Foresta et al, 2017 ; Cai and Li, 2020 ; Cannarella et al, 2021 ; Jockers and Liu, 2021 ; Leisegang et al, 2021 ; Assar et al, 2022 ; Mazzilli et al, 2022 ; Romejko et al, 2022 ) and nitric oxide signaling ( Radi, 2018 ; Carlström, 2021 ; Ledo et al, 2021 ; Mintz et al, 2021 ; Pourbagher-Shahri et al, 2021 ). Systemic microvascular ischemic endothelial dysfunction is a common condition associated with the pathogenesis of diseases ( Andersson et al, 2017 ; Jalnapurkar et al, 2021 ; Balistreri, 2022 ), hypoxia ( Chen et al, 2008 ; Jung et al, 2016 ; Chen et al, 2022a ), and vascular remodeling ( Yuan and Kevil, 2016 ; Rajendran P. et al, 2019 ; Huang et al, 2022 ). Loss of microvasculature (hypovascularity) implies a developing hypoxic milieu and suggests an important role for chronic hypoxia as an explanation for the progressive nature of fibrosis—the chronic hypoxia hypothesis ( Fine and Norman, 2008 ).…”

Progress in the Treatment of High Altitude Cerebral Edema: Targeting REDOX Homeostasis

“…4 Therefore, it is extremely sensitive to the hypobaric hypoxia environments at high altitudes. 5 HACE typically occurs in areas with altitudes ranging from 4500m to 5500m, is characterized by symptoms such as headache, ataxia, and altered mental status. 6,7 Though the incidence is low, it is a rapidly progressive and fatal disease.…”