Methylalpinumisoflavone Inhibits Hypoxia-inducible Factor-1 (HIF-1) Activation by Simultaneously Targeting Multiple Pathways

Liu, Yang; Veena, Coothan Kandaswamy; Morgan, Jody; Mohammed, Kaleem A.; Jekabsons, Mika B.; Nagle, Dale G.; Zhou, Yifeng

doi:10.1074/jbc.m806744200

Cited by 67 publications

(150 citation statements)

References 47 publications

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“…Moreover, the activation of HIF-1␣ has been observed in the ischemic myocardium (17), and the hypoxic induction of BNP mRNA expression has recently been described through a HIF-1-dependent mechanism in cultured adult rat cardiomyocytes and in different noncardiac human cell lines (39). In the present study, hypoxic cell cultures depicted enhanced HIF-1␣ activity, a phenomenon that was not seen when the cells were incubated with rotenone, a well-known inhibitor of HIF-1␣ stabilization in hypoxia (12,21,34). Rotenone abolishes the hypoxic stabilization of HIF-1␣ protein by inhibiting mitochondrial complex I activity (34), likely by blocking the electron flow proximally to complex III, thereby ablating the generation of reactive oxygen species during hypoxia (2).…”

Section: Discussioncontrasting

confidence: 56%

Hypoxia induces B-type natriuretic peptide release in cell lines derived from human cardiomyocytes

Casals

Ros²,

Sionís³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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B-type natriuretic peptide (BNP) is a peptide hormone of myocardial origin with significant cardioprotective properties. Patients with myocardial ischemia present with high levels of BNP in plasma and elevated expression in the myocardium. However, the molecular mechanisms of BNP induction in the ischemic myocardium are not well understood. The aim of the investigation was to assess whether myocardial hypoxia induces the production of BNP in human ventricular myocytes. To test the hypothesis that reduced oxygen tension can directly stimulate BNP gene expression and release in the absence of hemodynamic or neurohormonal stimuli, we used an in vitro model system of cultured human ventricular myocytes (AC16 cells). Cells were cultured under normoxic (21% O(2)) or hypoxic (5% O(2)) conditions for up to 48 h. The accumulation of BNP, atrial natriuretic peptide (ANP), and vascular endothelial growth factor (VEGF) was then measured. Hypoxia stimulated the protein release of BNP and VEGF but not ANP. In concordance, the increased mRNA levels of BNP and VEGF but not ANP were found on culturing AC16 cells under hypoxic conditions. The analysis of the transcriptional activity of the hypoxia-inducible factor 1 (HIF-1) in nuclear extracts showed that HIF-1 activity was induced under hypoxic conditions. Finally, the treatment of AC16 cells with the HIF-1 inhibitor rotenone in hypoxia inhibited BNP and VEGF release. In conclusion, these data indicate that hypoxia induces the synthesis and secretion of BNP in human ventricular myocytes, likely through HIF-1-enhanced transcriptional activity.

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Section: Discussioncontrasting

confidence: 56%

Hypoxia induces B-type natriuretic peptide release in cell lines derived from human cardiomyocytes

Casals

Ros²,

Sionís³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…Among the small molecule HIF-1 inhibitors that we and others have examined, compounds that disrupt the function of mitochondria selectively inhibited HIF-1 activation by hypoxia, relative to that by other stimuli (iron chelators, anoxia, etc.) 18,25,26. A T47D cell-based respiration study was performed to determine the effect of 1 on cellular oxygen consumption 26.…”

Section: Resultsmentioning

confidence: 99%

The Caulerpa Pigment Caulerpin Inhibits HIF-1 Activation and Mitochondrial Respiration

et al. 2009

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The transcription factor hypoxia-inducible factor-1 (HIF-1) represents an important molecular target for anticancer drug discovery. In a T47D cell-based reporter assay, the Caulerpa spp. algal pigment caulerpin (1) inhibited hypoxia-induced as well as 1,10-phenanthroline-induced HIF-1 activation. The angiogenic factor vascular endothelial growth factor (VEGF) is regulated by HIF-1. Caulerpin (10 μM) suppressed hypoxic induction of secreted VEGF protein and the ability of hypoxic T47D cell-conditioned media to promote tumor angiogenesis in vitro. Under hypoxic conditions, 1 (10 μM) blocked the induction of HIF-1α protein, the oxygen-regulated subunit that controls HIF-1 activity. Reactive oxygen species produced by mitochondrial complex III are believed to act as a signal of cellular hypoxia that leads to HIF-1α protein induction and activation. Further mechanistic studies revealed that 1 inhibits mitochondrial respiration at electron transport chain (ETC) complex I (NADH-ubiquinone oxidoreductase). Under hypoxic conditions, it is proposed that 1 may disrupt mitochondrial ROS-regulated HIF-1 activation and HIF-1 downstream target gene expression by inhibiting the transport or delivery of electrons to complex III.

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“…13,16 MDA-MB-231 and T47D cells loaded with TMRM for 2 h at 37 °C were treated with compounds for 30 min and live cell imaging was performed with an Axiovert 200M epifluorescence microscope (Zeiss).…”

Section: Methodsmentioning

confidence: 99%

Toxins in Botanical Dietary Supplements: Blue Cohosh Components Disrupt Cellular Respiration and Mitochondrial Membrane Potential

Datta¹,

Mahdi²,

Ali³

et al. 2013

J. Nat. Prod.

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Certain botanical dietary supplements have been associated with idiosyncratic organ-specific toxicity. Similar toxicological events, caused by drug-induced mitochondrial dysfunction, have forced the withdrawal or U.S. FDA “Black Box” warnings of major pharmaceuticals. To assess the potential mitochondrial liability of botanical dietary supplements, extracts from 352 authenticated plant samples used in traditional Chinese, Ayurvedic, and Western herbal medicine were evaluated for the ability to disrupt cellular respiration. Blue cohosh (Caulophyllum thalictroides) methanol extract exhibited mitochondriotoxic activity. Used by some U.S. midwives to help induce labor, blue cohosh has been associated with perinatal stroke, acute myocardial infarction, congestive heart failure, multiple organ injury, and neonatal shock. The potential link between mitochondrial disruption and idiosyncratic herbal intoxication prompted further examination. The C. thalictroides methanol extract and three saponins, cauloside A (1), saponin PE (2), and cauloside C (3) exhibited concentration- and time-dependent mitochondriotoxic activities. Upon treatment, cell respiration rate rapidly increased and then dramatically decreased within minutes. Mechanistic studies revealed that C. thalictroides constituents impair mitochondrial function by disrupting membrane integrity. These studies provide a potential etiological link between this mitochondria-sensitive form of cytotoxicity and idiosyncratic organ damage.

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Methylalpinumisoflavone Inhibits Hypoxia-inducible Factor-1 (HIF-1) Activation by Simultaneously Targeting Multiple Pathways

Cited by 67 publications

References 47 publications

Hypoxia induces B-type natriuretic peptide release in cell lines derived from human cardiomyocytes

Hypoxia induces B-type natriuretic peptide release in cell lines derived from human cardiomyocytes

The Caulerpa Pigment Caulerpin Inhibits HIF-1 Activation and Mitochondrial Respiration

Toxins in Botanical Dietary Supplements: Blue Cohosh Components Disrupt Cellular Respiration and Mitochondrial Membrane Potential

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