Substantial involvement of TRPM7 inhibition in the therapeutic effect of Ophiocordyceps sinensis on pulmonary hypertension

Keizo Hiraishi, Lin Hai Kurahara, Jianlin Feng, Aya Yamamura, Yuanyuan Cui, Eiji Yahiro, Hiroyasu Yokomise, Tetsuhiko Go, Kaori Ishikawa, Naoya Yokota, Atsushi Fujiwara, Miki Onitsuka, Kohtaro Abe, Shoji Ohga, Toru Satoh, Yasumasa Okada, Lixia Yue, Ryuji Inoue, Katsuya Hirano

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Ophiocordyceps sinensis (OCS), an entomopathogenic fungus, is known to exert antiproliferative and antitissue remodeling effects. Vascular remodeling and vasoconstriction play critical roles in the development of pulmonary hypertension (PH). The therapeutic potential of OCS for PH was investigated using rodent PH models, and cultured pulmonary artery endothelial and smooth muscle cells (PAECs and PASMCs), with a focus on the involvement of TRPM7. OCS ameliorated the development of PH, right ventricular hypertrophy and dysfunction in the monocrotaline-induced PH rats. The genetic knockout of TRPM7 attenuated the development of PH in mice with monocrotaline pyrrole-induced PH. TRPM7 was associated with medial hypertrophy and the plexiform lesions in rats and humans with PH. OCS suppressed proliferation of PASMCs derived from the PH patients. Ethanol extracts of OCS inhibited TRPM7-like current, TGF-β2-induced endothelial-mesenchymal transition, IL-6-induced STAT3 phosphorylation, and PDGF-induced Akt phosphorylation in PAECs or PASMCs. These inhibitory effects were recapitulated by either siRNA-mediated TRPM7 knockdown or treatment with TRPM7 antagonist FTY-720. OCS and FTY-720 induced vasorelaxation in the isolated normal human pulmonary artery. As a result, the present study proposes the therapeutic potential of OCS for the treatment of PH. The inhibition of TRPM7 is suggested to underlie the therapeutic effect of OCS.

Original languageEnglish
Pages (from-to)127-143
Number of pages17
JournalTranslational Research
Volume233
DOIs
Publication statusPublished - Jul 2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Public Health, Environmental and Occupational Health
  • Physiology (medical)
  • Biochemistry, medical

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