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  • 1
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    Online Resource
    Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension
    American Physiological Society ; 2015
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 308, No. 2 ( 2015-01-15), p. L208-L220
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 308, No. 2 ( 2015-01-15), p. L208-L220
    Abstract: Pulmonary vascular remodeling, mainly attributable to enhanced pulmonary arterial smooth muscle cell proliferation and migration, is a major cause for elevated pulmonary vascular resistance and pulmonary arterial pressure in patients with pulmonary hypertension. The signaling cascade through Akt, comprised of three isoforms (Akt1–3) with distinct but overlapping functions, is involved in regulating cell proliferation and migration. This study aims to investigate whether the Akt/mammalian target of rapamycin (mTOR) pathway, and particularly which Akt isoform, contributes to the development and progression of pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Compared with the wild-type littermates, Akt1 −/− mice were protected against the development and progression of chronic HPH, whereas Akt2 −/− mice did not demonstrate any significant protection against the development of HPH. Furthermore, pulmonary vascular remodeling was significantly attenuated in the Akt1 −/− mice, with no significant effect noted in the Akt2 −/− mice after chronic exposure to normobaric hypoxia (10% O 2 ). Overexpression of the upstream repressor of Akt signaling, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and conditional and inducible knockout of mTOR in smooth muscle cells were also shown to attenuate the rise in right ventricular systolic pressure and the development of right ventricular hypertrophy. In conclusion, Akt isoforms appear to have a unique function within the pulmonary vasculature, with the Akt1 isoform having a dominant role in pulmonary vascular remodeling associated with HPH. The PTEN/Akt1/mTOR signaling pathway will continue to be a critical area of study in the pathogenesis of pulmonary hypertension, and specific Akt isoforms may help specify therapeutic targets for the treatment of pulmonary hypertension.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00242.2014
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2015
    detail.hit.zdb_id: 1477300-4
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  • 2
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    Capsaicin-induced Ca 2+ signaling is enhanced via upregulated TRPV1 channels in pulmonary artery smooth muscle cells from patients with idiopathic PAH
    American Physiological Society ; 2017
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 312, No. 3 ( 2017-03-01), p. L309-L325
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 312, No. 3 ( 2017-03-01), p. L309-L325
    Abstract: Capsaicin is an active component of chili pepper and a pain relief drug. Capsaicin can activate transient receptor potential vanilloid 1 (TRPV1) channels to increase cytosolic Ca 2+ concentration ([Ca 2+ ] cyt ). A rise in [Ca 2+ ] cyt in pulmonary artery smooth muscle cells (PASMCs) is an important stimulus for pulmonary vasoconstriction and vascular remodeling. In this study, we observed that a capsaicin-induced increase in [Ca 2+ ] cyt was significantly enhanced in PASMCs from patients with idiopathic pulmonary arterial hypertension (IPAH) compared with normal PASMCs from healthy donors. In addition, the protein expression level of TRPV1 in IPAH PASMCs was greater than in normal PASMCs. Increasing the temperature from 23 to 43°C, or decreasing the extracellular pH value from 7.4 to 5.9 enhanced capsaicin-induced increases in [Ca 2+ ] cyt ; the acidity (pH 5.9)- and heat (43°C)-mediated enhancement of capsaicin-induced [Ca 2+ ] cyt increases were greater in IPAH PASMCs than in normal PASMCs. Decreasing the extracellular osmotic pressure from 310 to 200 mOsmol/l also increased [Ca 2+ ] cyt , and the hypo-osmolarity-induced rise in [Ca 2+ ] cyt was greater in IPAH PASMCs than in healthy PASMCs. Inhibition of TRPV1 (with 5′-IRTX or capsazepine) or knockdown of TRPV1 (with short hairpin RNA) attenuated capsaicin-, acidity-, and osmotic stretch-mediated [Ca 2+ ] cyt increases in IPAH PASMCs. Capsaicin induced phosphorylation of CREB by raising [Ca 2+ ] cyt , and capsaicin-induced CREB phosphorylation were significantly enhanced in IPAH PASMCs compared with normal PASMCs. Pharmacological inhibition and knockdown of TRPV1 attenuated IPAH PASMC proliferation. Taken together, the capsaicin-mediated [Ca 2+ ] cyt increase due to upregulated TRPV1 may be a critical pathogenic mechanism that contributes to augmented Ca 2+ influx and excessive PASMC proliferation in patients with IPAH.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00357.2016
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2017
    detail.hit.zdb_id: 1477300-4
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  • 3
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    Divergent changes of p53 in pulmonary arterial endothelial and smooth muscle cells involved in the development of pulmonary hypertension
    American Physiological Society ; 2019
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 316, No. 1 ( 2019-01-01), p. L216-L228
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 316, No. 1 ( 2019-01-01), p. L216-L228
    Abstract: The tumor-suppressive role of p53, a transcription factor that regulates the expression of many genes, has been linked to cell cycle arrest, apoptosis, and senescence. The noncanonical function or the pathogenic role of p53 has more recently been implicated in pulmonary vascular disease. We previously reported that rapid nuclear accumulation of hypoxia-inducible factor (HIF)-1α in pulmonary arterial smooth muscle cells (PASMCs) upregulates transient receptor potential channels and enhances Ca 2+ entry to increase cytosolic Ca 2+ concentration ([Ca 2+ ] cyt ). Also, we observed differences in HIF-1α/2α expression in PASMCs and pulmonary arterial endothelial cells (PAECs). Here we report that p53 is increased in PAECs, but decreased in PASMCs, isolated from mice with hypoxia-induced pulmonary hypertension (PH) and rats with monocrotaline (MCT)-induced PH (MCT-PH). The increased p53 in PAECs from rats with MCT-PH is associated with an increased ratio of Bax/Bcl-2, while the decreased p53 in PASMCs is associated with an increased HIF-1α. Furthermore, p53 is downregulated in PASMCs isolated from patients with idiopathic pulmonary arterial hypertension compared with PASMCs from normal subjects. Overexpression of p53 in normal PASMCs inhibits store-operated Ca 2+ entry (SOCE) induced by passive depletion of intracellularly stored Ca 2+ in the sarcoplasmic reticulum, while downregulation of p53 enhances SOCE. These data indicate that differentially regulated expression of p53 and HIF-1α/2α in PASMCs and PAECs and the cross talk between p53 and HIF-1α/2α in PASMCs and PAECs may play an important role in the development of PH via, at least in part, induction of PAEC apoptosis and PASMC proliferation.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00538.2017
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2019
    detail.hit.zdb_id: 1477300-4
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  • 4
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    ATP promotes cell survival via regulation of cytosolic [Ca 2+ ] and Bcl-2/Bax ratio in lung cancer cells
    American Physiological Society ; 2016
    In:  American Journal of Physiology-Cell Physiology Vol. 310, No. 2 ( 2016-01-15), p. C99-C114
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 310, No. 2 ( 2016-01-15), p. C99-C114
    Abstract: Adenosine triphosphate (ATP) is a ubiquitous extracellular messenger elevated in the tumor microenvironment. ATP regulates cell functions by acting on purinergic receptors (P2X and P2Y) and activating a series of intracellular signaling pathways. We examined ATP-induced Ca 2+ signaling and its effects on antiapoptotic (Bcl-2) and proapoptotic (Bax) proteins in normal human airway epithelial cells and lung cancer cells. Lung cancer cells exhibited two phases (transient and plateau phases) of increase in cytosolic [Ca 2+ ] ([Ca 2+ ] cyt ) caused by ATP, while only the transient phase was observed in normal cells. Removal of extracellular Ca 2+ eliminated the plateau phase increase of [Ca 2+ ] cyt in lung cancer cells, indicating that the plateau phase of [Ca 2+ ] cyt increase is due to Ca 2+ influx. The distribution of P2X (P2X1-7) and P2Y (P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 ) receptors was different between lung cancer cells and normal cells. Proapoptotic P2X 7 was nearly undetectable in lung cancer cells, which may explain why lung cancer cells showed decreased cytotoxicity when treated with high concentration of ATP. The Bcl-2/Bax ratio was increased in lung cancer cells following treatment with ATP; however, the antiapoptotic protein Bcl-2 demonstrated more sensitivity to ATP than proapoptotic protein Bax. Decreasing extracellular Ca 2+ or chelating intracellular Ca 2+ with BAPTA-AM significantly inhibited ATP-induced increase in Bcl-2/Bax ratio, indicating that a rise in [Ca 2+ ] cyt through Ca 2+ influx is the critical mediator for ATP-mediated increase in Bcl-2/Bax ratio. Therefore, despite high ATP levels in the tumor microenvironment, which would induce cell apoptosis in normal cells, the decreased P2X 7 and elevated Bcl-2/Bax ratio in lung cancer cells may enable tumor cells to survive. Increasing the Bcl-2/Bax ratio by exposure to high extracellular ATP may, therefore, be an important selective pressure promoting transformation and cancer progression.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00092.2015
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2016
    detail.hit.zdb_id: 1477334-X
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  • 5
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    Pathogenic role of calcium-sensing receptors in the development and progression of pulmonary hypertension
    American Physiological Society ; 2016
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 310, No. 9 ( 2016-05-01), p. L846-L859
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 310, No. 9 ( 2016-05-01), p. L846-L859
    Abstract: An increase in cytosolic free Ca 2+ concentration ([Ca 2+ ] cyt ) in pulmonary arterial smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and a critical stimulation for PASMC proliferation and migration. Previously, we demonstrated that expression and function of calcium sensing receptors (CaSR) in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH) and animals with experimental pulmonary hypertension (PH) were greater than in PASMC from normal subjects and control animals. However, the mechanisms by which CaSR triggers Ca 2+ influx in PASMC and the implication of CaSR in the development of PH remain elusive. Here, we report that CaSR functionally interacts with TRPC6 to regulate [Ca 2+ ] cyt in PASMC. Downregulation of CaSR or TRPC6 with siRNA inhibited Ca 2+ -induced [Ca 2+ ] cyt increase in IPAH-PASMC (in which CaSR is upregulated), whereas overexpression of CaSR or TRPC6 enhanced Ca 2+ -induced [Ca 2+ ] cyt increase in normal PASMC (in which CaSR expression level is low). The upregulated CaSR in IPAH-PASMC was also associated with enhanced Akt phosphorylation, whereas blockade of CaSR in IPAH-PASMC attenuated cell proliferation. In in vivo experiments, deletion of the CaSR gene in mice ( casr −/− ) significantly inhibited the development and progression of experimental PH and markedly attenuated acute hypoxia-induced pulmonary vasoconstriction. These data indicate that functional interaction of upregulated CaSR and upregulated TRPC6 in PASMC from IPAH patients and animals with experimental PH may play an important role in the development and progression of sustained pulmonary vasoconstriction and pulmonary vascular remodeling. Blockade or downregulation of CaSR and/or TRPC6 with siRNA or miRNA may be a novel therapeutic strategy to develop new drugs for patients with pulmonary arterial hypertension.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00050.2016
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2016
    detail.hit.zdb_id: 1477300-4
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  • 6
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    Endothelial HIF-2α Contributes to Severe Pulmonary Hypertension by Inducing Endothelial-to-Mesenchymal Transition
    American Physiological Society ; 2017
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology ( 2017-10-26), p. ajplung.00096.2-
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, ( 2017-10-26), p. ajplung.00096.2-
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00096.2017
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2017
    detail.hit.zdb_id: 1477300-4
    SSG: 12
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  • 7
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    Upregulated expression of STIM2, TRPC6, and Orai2 contributes to the transition of pulmonary arterial smooth muscle cells from a contractile to proliferative phenotype
    American Physiological Society ; 2015
    In:  American Journal of Physiology-Cell Physiology Vol. 308, No. 8 ( 2015-04-15), p. C581-C593
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 308, No. 8 ( 2015-04-15), p. C581-C593
    Abstract: Pulmonary arterial hypertension (PAH) is a progressive disease that, if left untreated, eventually leads to right heart failure and death. Elevated pulmonary arterial pressure (PAP) in patients with PAH is mainly caused by an increase in pulmonary vascular resistance (PVR). Sustained vasoconstriction and excessive pulmonary vascular remodeling are two major causes for elevated PVR in patients with PAH. Excessive pulmonary vascular remodeling is mediated by increased proliferation of pulmonary arterial smooth muscle cells (PASMC) due to PASMC dedifferentiation from a contractile or quiescent phenotype to a proliferative or synthetic phenotype. Increased cytosolic Ca 2+ concentration ([Ca 2+ ] cyt ) in PASMC is a key stimulus for cell proliferation and this phenotypic transition. Voltage-dependent Ca 2+ entry (VDCE) and store-operated Ca 2+ entry (SOCE) are important mechanisms for controlling [Ca 2+ ] cyt . Stromal interacting molecule proteins (e.g., STIM2) and Orai2 both contribute to SOCE and we have previously shown that STIM2 and Orai2, specifically, are upregulated in PASMC from patients with idiopathic PAH and from animals with experimental pulmonary hypertension in comparison to normal controls. In this study, we show that STIM2 and Orai2 are upregulated in proliferating PASMC compared with contractile phenotype of PASMC. Additionally, a switch in Ca 2+ regulation is observed in correlation with a phenotypic transition from contractile PASMC to proliferative PASMC. PASMC in a contractile phenotype or state have increased VDCE, while in the proliferative phenotype or state PASMC have increased SOCE. The data from this study indicate that upregulation of STIM2 and Orai2 is involved in the phenotypic transition of PASMC from a contractile state to a proliferative state; the enhanced SOCE due to upregulation of STIM2 and Orai2 plays an important role in PASMC proliferation.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00202.2014
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2015
    detail.hit.zdb_id: 1477334-X
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  • 8
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    Flow shear stress enhances intracellular Ca 2+ signaling in pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension
    American Physiological Society ; 2014
    In:  American Journal of Physiology-Cell Physiology Vol. 307, No. 4 ( 2014-08-15), p. C373-C383
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 307, No. 4 ( 2014-08-15), p. C373-C383
    Abstract: An increase in cytosolic Ca 2+ concentration ([Ca 2+ ] cyt ) in pulmonary arterial smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and an important stimulus for pulmonary arterial medial hypertrophy in patients with idiopathic pulmonary arterial hypertension (IPAH). Vascular smooth muscle cells (SMC) sense the blood flow shear stress through interstitial fluid driven by pressure or direct exposure to blood flow in case of endothelial injury. Mechanical stimulus can increase [Ca 2+ ] cyt . Here we report that flow shear stress raised [Ca 2+ ] cyt in PASMC, while the shear stress-mediated rise in [Ca 2+ ] cyt and the protein expression level of TRPM7 and TRPV4 channels were significantly greater in IPAH-PASMC than in normal PASMC. Blockade of TRPM7 by 2-APB or TRPV4 by Ruthenium red inhibited shear stress-induced rise in [Ca 2+ ] cyt in normal and IPAH-PASMC, while activation of TRPM7 by bradykinin or TRPV4 by 4αPDD induced greater increase in [Ca 2+ ] cyt in IPAH-PASMC than in normal PASMC. The bradykinin-mediated activation of TRPM7 also led to a greater increase in [Mg 2+ ] cyt in IPAH-PASMC than in normal PASMC. Knockdown of TRPM7 and TRPV4 by siRNA significantly attenuated the shear stress-mediated [Ca 2+ ] cyt increases in normal and IPAH-PASMC. In conclusion, upregulated mechanosensitive channels (e.g., TRPM7, TRPV4, TRPC6) contribute to the enhanced [Ca 2+ ] cyt increase induced by shear stress in PASMC from IPAH patients. Blockade of the mechanosensitive cation channels may represent a novel therapeutic approach for relieving elevated [Ca 2+ ] cyt in PASMC and thereby inhibiting sustained pulmonary vasoconstriction and pulmonary vascular remodeling in patients with IPAH.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00115.2014
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2014
    detail.hit.zdb_id: 1477334-X
    SSG: 12
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