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Pyk2 aggravates hypoxia-induced pulmonary hypertension by activating HIF-1α.

Abstract
Pulmonary arterial hypertension (PAH) is a refractory disease characterized by uncontrolled vascular remodeling and elevated pulmonary arterial pressure. Although synthetic inhibitors of some tyrosine kinases have been used to treat PAH, their therapeutic efficacies and safeties remain controversial. Thus, the establishment of novel therapeutic targets based on the molecular pathogenesis underlying PAH is a clinically urgent issue. In the present study, we demonstrated that proline-rich tyrosine kinase 2 (Pyk2), a nonreceptor type protein tyrosine kinase, plays a crucial role in the pathogenesis of pulmonary hypertension (PH) using an animal model of hypoxia-induced PH. Resistance to hypoxia-induced PH was markedly higher in Pyk2-deficient mice than in wild-type mice. Pathological investigations revealed that medial thickening of the pulmonary arterioles, which is a characteristic of hypoxia-induced PH, was absent in Pyk2-deficient mice, suggesting that Pyk2 is involved in the hypoxia-induced aberrant proliferation of vascular smooth muscle cells in hypoxia-induced PH. In vitro experiments using human pulmonary smooth muscle cells showed that hypoxic stress increased the proliferation and migration of cells in a Pyk2-dependent manner. We also demonstrated that Pyk2 plays a crucial role in ROS generation during hypoxic stress and that this Pyk2-dependent generation of ROS is necessary for the activation of hypoxia-inducible factor-1α, a key molecule in the pathogenesis of hypoxia-induced PH. In summary, the results of the present study reveal that Pyk2 plays an important role in the pathogenesis of hypoxia-induced PH. Therefore, Pyk2 may represent a promising therapeutic target for PAH in a clinical setting.
AuthorsKuniyoshi Fukai, Akihiro Nakamura, Atsushi Hoshino, Naohiko Nakanishi, Yoshifumi Okawa, Makoto Ariyoshi, Satoshi Kaimoto, Motoki Uchihashi, Kazunori Ono, Shuhei Tateishi, Koji Ikeda, Takehiro Ogata, Tomomi Ueyama, Satoaki Matoba
JournalAmerican journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 308 Issue 8 Pg. H951-9 (Apr 15 2015) ISSN: 1522-1539 [Electronic] United States
PMID25659487 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 the American Physiological Society.
Chemical References
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Reactive Oxygen Species
  • Focal Adhesion Kinase 2
  • Ptk2b protein, mouse
Topics
  • Animals
  • Arterioles (cytology, metabolism, physiology)
  • Cell Hypoxia
  • Cell Movement
  • Cell Proliferation
  • Cells, Cultured
  • Focal Adhesion Kinase 2 (genetics, metabolism)
  • Humans
  • Hypertension, Pulmonary (etiology, metabolism, physiopathology)
  • Hypoxia (complications)
  • Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
  • Lung (blood supply)
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Smooth, Vascular (metabolism, physiology)
  • Myocytes, Smooth Muscle (metabolism, physiology)
  • Reactive Oxygen Species (metabolism)

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