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  • Huang, Chung-Chi  (4)
  • Pang, Jong-Hwei S.  (4)
  • 1
    Online Resource
    Online Resource
    Cathepsin S promotes the development of pulmonary arterial hypertension
    American Physiological Society ; 2019
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 317, No. 1 ( 2019-07-01), p. L1-L13
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 317, No. 1 ( 2019-07-01), p. L1-L13
    Abstract: Cysteine cathepsin proteases play critical roles in cardiovascular disease progression and are implicated in extracellular matrix (ECM) degradation. Patients with pulmonary arterial hypertension (PAH) exhibit increased elastase production by pulmonary arterial smooth muscle cells (PASMCs), which is related to the degradation of elastic fibers and pulmonary vascular remodeling. However, the mechanism by which cathepsins regulate the ECM and PASMC proliferation in PAH remains unclear. We hypothesized that cathepsin proteases in PASMCs promote the development of PAH. Here, we show overexpression of cathepsin S (Cat S) and degradation of elastic laminae in the lungs of patients with idiopathic PAH and in the PASMCs of monocrotaline-induced PAH model (MCT-PAH) rats. In addition, pulmonary hypertension can be treated in MCT-PAH rats by administering a selective Cat S inhibitor, Millipore-219393, which stimulates peroxisome proliferator-activated receptor-γ (PPARγ) to inhibit the expression of Cat S, thus suppressing the proliferation and migration of MCT-PAH PASMCs. We then reduced Cat S or PPARγ expression by using small interfering RNA in human PASMCs to demonstrate a mechanistic link between Cat S signaling and PPARγ protein, and the results suggest that PPARγ is upstream of Cat S signaling. In conclusion, the activity of Cat S in pulmonary vascular remodeling and degradation of elastin fibers through the disruption of PPARγ is pathophysiologically significant in PAH.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00530.2018
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2019
    detail.hit.zdb_id: 1477300-4
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Prostanoid EP 4 agonist L-902,688 activates PPARγ and attenuates pulmonary arterial hypertension
    American Physiological Society ; 2018
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 314, No. 3 ( 2018-03-01), p. L349-L359
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 314, No. 3 ( 2018-03-01), p. L349-L359
    Abstract: Prostacyclin agonists that bind the prostacyclin receptor (IP) to stimulate cAMP synthesis are effective vasodilators for the treatment of idiopathic pulmonary arterial hypertension (IPAH), but this signaling may occur through nuclear peroxisome proliferator-activated receptor-γ (PPARγ). There is evidence of scant IP and PPARγ expression but stable prostanoid EP 4 receptor (EP 4 ) expression in IPAH patients. Both IP and EP 4 functionally couple with stimulatory G protein (G s ), which activates signal transduction. We investigated the effect of an EP 4 -specific agonist on pulmonary arterial remodeling and its regulatory mechanisms in pulmonary arterial smooth muscle cells (PASMCs). Immunoblotting evealed IP, EP 4 , and PPARγ expression in human pulmonary arterial hypertension (PAH) and monocrotaline (MCT)-induced PAH rat lung tissue. Isolated PASMCs from MCT-induced PAH rats (MCT-PASMCs) were treated with L-902,688, a selective EP 4 agonist, to investigate the anti-vascular remodeling effect. Scant expression of IP and PPARγ but stable expression of EP 4 was observed in IPAH patient lung tissues and MCT-PASMCs. L-902,688 inhibited IP-insufficient MCT-PASMC proliferation and migration by activating PPARγ in a time- and dose-dependent manner, but these effects were reversed by AH-23848 (an EP 4 antagonist) and H-89 [a protein kinase A (PKA) inhibitor], highlighting the crucial role of PPARγ in the activity of this EP 4 agonist. L-902,688 attenuated pulmonary arterial remodeling in hypoxic PAH mice and MCT-induced PAH rats; therefore, we conclude that the selective EP 4 agonist L-902,688 reverses vascular remodeling by activating PPARγ. This study identified a novel EP 4 -PKA-PPARγ pathway, and we propose EP 4 as a potential therapeutic target for PAH.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00245.2017
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2018
    detail.hit.zdb_id: 1477300-4
    SSG: 12
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  • 3
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    Author Correction: Prostaglandin E1 Attenuates Pulmonary Artery Remodeling by Activating Phosphorylation of CREB and the PTEN Signaling Pathway
    Springer Science and Business Media LLC ; 2018
    In:  Scientific Reports Vol. 8, No. 1 ( 2018-07-24)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2018-07-24)
    Abstract: A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-018-28951-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2615211-3
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  • 4
    Online Resource
    Online Resource
    Prostaglandin E1 Attenuates Pulmonary Artery Remodeling by Activating Phosphorylation of CREB and the PTEN Signaling Pathway
    Springer Science and Business Media LLC ; 2017
    In:  Scientific Reports Vol. 7, No. 1 ( 2017-08-30)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 7, No. 1 ( 2017-08-30)
    Abstract: The depletion of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and phosphatase and tensin homolog (PTEN) is the critical mediator of pulmonary arterial hypertension (PAH). We hypothesized that the activation of phosphorylated CREB (pCREB) and PTEN could inhibit the AKT signaling pathway to attenuate pulmonary arterial remodeling in rats with monocrotaline-induced PAH. We observed decreased PTEN and pCREB in idiopathic PAH versus control tissue. We reduced PTEN using small interfering RNA in human control pulmonary arterial smooth muscle cells (PASMCs) and observed an increase in pAKT. Consistent with PTEN knockdown in PASMCs, prostaglandin E1 (PGE1) induced pCREB expression to stimulate PTEN protein expression and inhibited pAKT in a time- and dose-dependent manner. The enhanced proliferation and migration of PASMCs following PTEN knockdown were significantly inhibited by PGE1 treatment. The PGE1-induced elevation of PTEN expression in PTEN-depleted PASMCs was decreased by the application of a PKA inhibitor and a CBP-CREB interaction inhibitor. Supplementation with a novel emulsion composition comprising PGE1 in rats with monocrotaline-induced PAH prevented pulmonary arterial remodeling and improved hemodynamics via the induced expression of PTEN. We conclude that PGE1 recruits pCREB/PTEN to decrease the migration and proliferation of PASMCs associated with PAH. This finding elucidates a relevant underlying mechanism of the PGE1/CREB/PTEN signaling pathway to prevent progressive PAH.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-017-09707-y
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2615211-3
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