Type 2 inositol 1,4,5-trisphosphate receptor inhibits the progression of pulmonary arterial hypertension via calcium signaling and apoptosis

Akimichi Shibata, Keiko Uchida, Kazuki Kodo, Takayuki Miyauchi, Katsuhiko Mikoshiba, Takao Takahashi, Hiroyuki Yamagishi

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease associated with vasoconstriction and remodeling. Intracellular Ca 2+ signaling regulates the contraction of pulmonary arteries and the proliferation of pulmonary arterial smooth muscle cells (PASMCs); however, it is not clear which molecules related to Ca 2+ signaling contribute to the progression of PAH. In this study, we found the specific expression of type 2 inositol 1,4,5-trisphosphate receptor (IP 3 R2), which is an intracellular Ca 2+ release channel, on the sarco/endoplasmic reticulum in mouse PASMCs, and demonstrated its inhibitory role in the progression of PAH using a chronic hypoxia-induced PAH mouse model. After chronic hypoxia exposure, IP 3 R2 −/− mice exhibited the significant aggravation of PAH, as determined by echocardiography and right ventricular hypertrophy, with significantly greater medial wall thickness by immunohistochemistry than that of wild-type mice. In IP 3 R2 −/− murine PASMCs with chronic hypoxia, a TUNEL assay revealed the significant suppression of apoptosis, whereas there was no significant change in proliferation. Thapsigargin-induced store-operated Ca 2+ entry (SOCE) was significantly enhanced in IP 3 R2 −/− PASMCs in both normoxia and hypoxia based on in vitro fluorescent Ca 2+ imaging. Furthermore, the enhancement of SOCE in IP 3 R2 −/− PASMCs was remarkably suppressed by the addition of DPB162-AE, an inhibitor of the stromal-interacting molecule (STIM)–Orai complex which is about 100 times more potent than 2-APB. Our results indicate that IP 3 R2 may inhibit the progression of PAH by promoting apoptosis and inhibiting SOCE via the STIM–Orai pathway in PASMCs. These findings suggest a previously undetermined role of IP 3 R in the development of PAH and may contribute to the development of targeted therapies.

Original languageEnglish
Pages (from-to)724-734
Number of pages11
JournalHeart and vessels
Volume34
Issue number4
DOIs
Publication statusPublished - 2019 Apr 15

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Keywords

  • Apoptosis
  • Chronic hypoxia
  • Pulmonary artery smooth muscle cells
  • Store-operated calcium entry

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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