MicroRNA-210 suppresses glucocorticoid receptor expression in response to hypoxia in fetal rat cardiomyocytes

Abstract

Hypoxia is a common intrauterine stressor, often resulting in intrauterine growth restriction and increased risk for cardiovascular disease later in life. The aim of this work was to test the hypothesis that microRNA-210 (miR-210) mediates the detrimental suppression of glucocorticoid receptor (GR) in response to hypoxia in fetal rat cardiomyocytes. Cardiomyocytes isolated from gestational day 21 Sprague Dawley fetal rats showed increased miR-210 levels and reduced GR abundance after exposure to ex vivo hypoxia (1% O2). In regard to mechanisms, the different contributions of hypoxia response elements (HREs) motifs in the regulation of miR-210 promoter activity and the miR-210-mediated repression of GR expression were determined in rat embryonic heart-derived myogenic cell line H9c2. Moreover, using a cell culture-based model of hypoxia-reoxygenation injury, we assessed the cytotoxic effects of GR suppression under hypoxic conditions. The results showed that hypoxia induced HIF-1α-dependent miR-210 production, as well as miR-210-mediated GR suppression, in cardiomyocytes. Furthermore, inhibition or knockdown of GR exacerbated cell death in response to hypoxia-reoxygenation injury. Altogether, the present study demonstrates that the HIF-1α-dependent miR-210-mediated suppression of GR in fetal rat cardiomyocytes increases cell death in response to hypoxia, providing novel evidence for a possible mechanistic link between fetal hypoxia and programming of ischemic-sensitive phenotype in the developing heart.

Scutellaria barbata D. Don (SBD) protects oxygen glucose deprivation/reperfusion-induced injuries of PC12 cells by up-regulating Nrf2

“…It has been proved that the PI3K/AKT signalling pathway participates in the regulation of the pathological process of cerebral ischemia injury [33][34][35]. In addition, several studies have reported that Nrf2 is a downstream regulator of PI3K/AKT pathway [18,36]. Thus, we further explored the effect of SBD pretreatment on the activation of PI3K/AKT pathway.…”

Mitochondrial MiRNA in Cardiovascular Function and Disease

“…It should be noted that the controversial effects of miR-210 on cardiomyocytes under hypoxia conditions have been reported. Sun et al and our previous study demonstrated that miR-210 induced oxidative stress, inhibited mitochondrial function, and promoted cell death in fetal cardiomyocytes [89,90]. However, Mutharasan et al showed that overexpression of miR-210 reduced fetal cardiomyocyte death in response to oxidative stress and reduced ROS production through Akt-and p53-dependent pathways [91].…”

Fetal Hypoxia Impacts on Proliferation and Differentiation of Sca-1+ Cardiac Progenitor Cells and Maturation of Cardiomyocytes: A Role of MicroRNA-210

“…To measure the proliferation rates of Sca-1 + CPCs, cells were dissociated using 0.25% Trypsin (Gibco) for cell counting after culture under normoxia and hypoxia. Once the cell confluence reached~85%, Sca-1 + CPCs were transfected with 50 nM LNA-anti-microRNA-210 (Exiqon, Germantown, MD, USA) or LNA scramble control (Exiqon) using optiMEM for 18 h [5]. Differentiation experiments were initiated with non-transfected and transfected Sca-1 + CPCs under normoxic (21% oxygen) and hypoxic (1% oxygen) conditions, respectively.…”

“…CHDs affect more than one million adults in the United States alone [1,2]. Apart from a minority of CHD cases caused by genetic factors, the majority of CHD cases have been reported to be tightly linked with environmental factors including smoking, diabetes mellitus, obesity, and hypoxia [3][4][5][6]. Pregnancy at high altitude, with diseases of anemia, pulmonary or heart problems and preeclampsia, or placental insufficiency has been reported to cause hypoxic stress to the fetal development and increase the occurrence of CHDs [2,7,8].…”

“…MicroRNA-210 is regarded as a master microRNA of the hypoxic response due to its high popularity in all the tested cell types [27,28]. Our previous studies have shown that hypoxia promotes the ischemia-sensitive phenotype by increasing microRNA-210 expression during fetal heart development [5,29]. It is likely that microRNA-210 modulates CPC cell fate under hypoxia.…”