Stress and Adrenergic Function: HIF1α, a Potential Regulatory Switch

Wong, Dona L.; Tai, T.C.; Wong-Faull, David C.; Claycomb, Robert; Siddall, Brenda; Bell, Rose Ann; Květňanský, Richard

doi:10.1007/s10571-010-9567-z

Cited by 18 publications

(19 citation statements)

References 52 publications

(57 reference statements)

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“…S-adenosylmethionine is the methyl donor with methylation catalyzed by PNMT. Early studies in rats and mice demonstrated that Epi is regulated in vivo by stress through genetic control of its biosynthesis by PNMT (reviewed in Kvetnansky et al 2009;Wong et al 2010). In the rat adrenal medulla, IMMO stress increases both PNMT mRNA and protein expression with similar patterns and extent of change (Tai et al 2007;Viskupic et al 1994;Wong et al 2002Wong et al , 2004Wong et al , 2008.…”

Section: Epi Regulation By Stressmentioning

confidence: 99%

“…Research in rats indicates that critical transcriptional activators of PNMT (see Wong et al 2010, for review) include early growth response gene-1 (Egr-1), specificity protein 1 (Sp1), glucocorticoid receptor (GR), glial cell missing-like factor (GCM l ), activating protein 2 (AP-2), and cMyc-activating factor (MAZ) with response elements (REs) for all residing within the proximal -893 bp of the gene promoter sequence upstream of the site of transcription initiation (?1, Fig. 3) (Ebert et al 1994Ebert and Wong 1995;Her et al 1999Her et al , 2003Ross et al 1990;Tai et al 2002;Tai and Wong 2003;Wong et al 1998).…”

Section: Epi Regulation By Stressmentioning

confidence: 99%

“…Other types of stress also activate PNMT, including cold (4°C), exercise and hypoglycemia (see Kvetnansky et al 2009;Wong et al 2010). However, the magnitude of change in PNMT expression is highly dependent on the type of stress (psychological, physical, or physiological) and its intensity.…”

Section: Epi Regulation By Stressmentioning

confidence: 99%

“…Signaling mechanisms underlying hypoxic activation of the PNMT gene have also been identified by examining the effects of selective signaling inhibitors on hypoxic activation of PNMT promoter-driven reporter gene expression in the PC12 cells and/or protein kinase A (PKA)-or phospholipase C (PLC)-deficient PC12 cells Wong et al 2010). Hypoxia initiates signaling through the two major bifurcating pathways, cAMP-PKA and PLC.…”

Section: Epi Regulation By Stressmentioning

confidence: 99%

“…Our interests focus on the potential role that the stress hormone Epi, which is itself regulated by stress via genetic control of its biosynthetic enzyme, phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28) (Wong and Tank 2007;Wong et al 2008Wong et al , 2010, may play in initiating illness. While Epi historically has been associated with short-term stress responsiveness, it has also been linked to many long-term, stress-induced illnesses.…”

Section: Introductionmentioning

confidence: 99%

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Epinephrine: A Short- and Long-Term Regulator of Stress and Development of Illness

et al. 2011

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Epinephrine (Epi), which initiates short-term responses to cope with stress, is, in part, stress-regulated via genetic control of its biosynthetic enzyme, phenylethanolamine N-methyltransferase (PNMT). In rats, immobilization (IMMO) stress activates the PNMT gene in the adrenal medulla via Egr-1 and Sp1 induction. Yet, elevated Epi induced by acute and chronic stress is associated with stress induced, chronic illnesses of cardiovascular, immune, cancerous, and behavioral etiologies. Major sources of Epi include the adrenal medulla and brainstem. Although catecholamines do not cross the blood-brain barrier, circulating Epi from the adrenal medulla may communicate with the central nervous system and stress circuitry by activating vagal nerve β-adrenergic receptors to release norepinephrine, which could then stimulate release of the same from the nucleus tractus solitarius and locus coeruleus. In turn, the basal lateral amygdala (BLA) may activate to stimulate afferents to the hypothalamus, neocortex, hippocampus, caudate nucleus, and other brain regions sequentially. Recently, we have shown that repeated IMMO or force swim stress may evoke stress resiliency, as suggested by changes in expression and extinction of fear memory in the fear-potentiated startle paradigm. However, concomitant adrenergic changes seem stressor dependent. Present studies aim to identify stressful conditions that elicit stress resiliency versus stress sensitivity, with the goal of developing a model to investigate the potential role of Epi in stress-associated illness. If chronic Epi over expression does elicit illness, possibilities for alternative therapeutics exist through regulating stress-induced Epi expression, adrenergic receptor function and/or corticosteroid effects on Epi, adrenergic receptors and the stress axis.

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Section: Epi Regulation By Stressmentioning

confidence: 99%

Section: Epi Regulation By Stressmentioning

confidence: 99%

Section: Epi Regulation By Stressmentioning

confidence: 99%

Section: Epi Regulation By Stressmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epinephrine: A Short- and Long-Term Regulator of Stress and Development of Illness

et al. 2011

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Cellular density‐dependent down‐regulation of EP4 prostanoid receptors via the up‐regulation of hypoxia‐inducible factor‐1α in HCA‐7 human colon cancer cells

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Yoshida

Seira

et al. 2014

Pharmacology Res & Perspec

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Increases in prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2) levels are features of colon cancer. Among the different E-type prostanoid receptor subtypes, EP4 receptors are considered to play a crucial role in carcinogenesis by, for example, inducing COX-2 when stimulated with PGE2. However, EP4 receptor levels and PGE2-induced cellular responses are inconsistent among the cellular conditions. Therefore, the connections responsible for the expression of EP4 receptors were investigated in the present study by focusing on cell density-induced hypoxia-inducible factor-1α (HIF-1α). The expression of EP4 receptors was examined using immunoblot analysis, quantitative polymerase chain reaction, and reporter gene assays in HCA-7 human colon cancer cells with different cellular densities. The involvement of HIF-1α and its signaling pathways were also examined by immunoblot analysis, reporter gene assays, and with siRNA. We here demonstrated that EP4 receptors as well as EP4 receptor-mediated COX-2 expression levels decreased with an increase in cellular density. In contrast, HIF-1α levels increased in a cellular density-dependent manner. The knockdown of HIF-1α by siRNA restored the expression of EP4 receptors and EP4 receptor-mediated COX-2 in cells at a high density. Thus, the cellular density-dependent increase observed in HIF-1α expression levels reduced the expression of COX-2 by decreasing EP4 receptor levels. This novel regulation mechanism for the expression of EP4 receptors by HIF-1α may provide an explanation for the inconsistent actions of PGE2. The expression levels of EP4 receptors may vary depending on cellular density, which may lead to the differential activation of their signaling pathways by PGE2. Thus, cellular density-dependent PGE2-mediated signaling may determine the fate/stage of cancer cells, i.e., the surrounding environments could define the fate/stage of malignancies associated with colon cancer.

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HIF2α regulates the synthesis and release of epinephrine in the adrenal medulla

et al. 2021

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The adrenal gland and its hormones regulate numerous fundamental biological processes; however, the impact of hypoxia signaling on adrenal function remains poorly understood. Here, we reveal that deficiency of HIF (hypoxia inducible factors) prolyl hydroxylase domain protein-2 (PHD2) in the adrenal medulla of mice results in HIF2α-mediated reduction in phenylethanolamine N-methyltransferase (PNMT) expression, and consequent reduction in epinephrine synthesis. Simultaneous loss of PHD2 in renal erythropoietin (EPO)-producing cells (REPCs) stimulated HIF2α-driven EPO overproduction, excessive RBC formation (erythrocytosis), and systemic hypoglycemia, which is necessary and sufficient to enhance exocytosis of epinephrine from the adrenal medulla. Based on these results, we propose that the PHD2-HIF2α axis in the adrenal medulla regulates the synthesis of epinephrine, whereas in REPCs, it indirectly induces the release of this hormone. Our findings are also highly relevant to the testing of small molecule PHD inhibitors in phase III clinical trials for patients with renal anemia. Key messages HIF2α and not HIF1α modulates PNMT during epinephrine synthesis in chromaffin cells. The PHD2-HIF2α-EPO axis induces erythrocytosis and hypoglycemia. Reduced systemic glucose facilitates exocytosis of epinephrine from adrenal gland.

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Stress and Adrenergic Function: HIF1α, a Potential Regulatory Switch

Cited by 18 publications

References 52 publications

Epinephrine: A Short- and Long-Term Regulator of Stress and Development of Illness

Epinephrine: A Short- and Long-Term Regulator of Stress and Development of Illness

Cellular density‐dependent down‐regulation of EP4 prostanoid receptors via the up‐regulation of hypoxia‐inducible factor‐1α in HCA‐7 human colon cancer cells

HIF2α regulates the synthesis and release of epinephrine in the adrenal medulla

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