Identification of Celastramycin as a Novel Therapeutic Agent for Pulmonary Arterial Hypertension: High-Throughput Screening of 5562 Compounds

Ryo Kurosawa, Kimio Satoh, Nobuhiro Kikuchi, Haruhisa Kikuchi, Daisuke Saigusa, Md Elias Al-Mamun, Mohammad A.H. Siddique, Junichi Omura, Taijyu Satoh, Shinichiro Sunamura, Masamichi Nogi, Kazuhiko Numano, Satoshi Miyata, Akira Uruno, Kuniyuki Kano, Yotaro Matsumoto, Takayuki Doi, Junken Aoki, Yoshiteru Oshima, Masayuki YamamotoHiroaki Shimokawa

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

Rationale: Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) accompanying increased production of inflammatory factors and adaptation of the mitochondrial metabolism to a hyperproliferative state. However, all the drugs in clinical use target pulmonary vascular dilatation, which may not be effective for patients with advanced PAH. Objective: We aimed to discover a novel drug for PAH that inhibits PASMC proliferation. Methods and Results: We screened 5562 compounds from original library using high-Throughput screening system to discover compounds which inhibit proliferation of PASMCs from patients with PAH (PAH-PASMCs). We found that celastramycin, a benzoyl pyrrole-Type compound originally found in a bacteria extract, inhibited the proliferation of PAH-PASMCs in a dose-dependent manner with relatively small effects on PASMCs from healthy donors. Then, we made 25 analogs of celastramycin and selected the lead compound, which significantly inhibited cell proliferation of PAH-PASMCs and reduced cytosolic reactive oxygen species levels. Mechanistic analysis demonstrated that celastramycin reduced the protein levels of HIF-1 (hypoxia-inducible factor 1), which impairs aerobic metabolism, and κB (nuclear factor-κB), which induces proinflammatory signals, in PAH-PASMCs, leading to reduced secretion of inflammatory cytokine. Importantly, celastramycin treatment reduced reactive oxygen species levels in PAH-PASMCs with increased protein levels of Nrf2 (nuclear factor erythroid 2-related factor 2), a master regulator of cellular response against oxidative stress. Furthermore, celastramycin treatment improved mitochondrial energy metabolism with recovered mitochondrial network formation in PAH-PASMCs. Moreover, these celastramycin-mediated effects were regulated by ZFC3H1 (zinc finger C3H1 domain-containing protein), a binding partner of celastramycin. Finally, celastramycin treatment ameliorated pulmonary hypertension in 3 experimental animal models, accompanied by reduced inflammatory changes in the lungs. Conclusions: These results indicate that celastramycin ameliorates pulmonary hypertension, reducing excessive proliferation of PAH-PASMCs with less inflammation and reactive oxygen species levels, and recovered mitochondrial energy metabolism. Thus, celastramycin is a novel drug for PAH that targets antiproliferative effects on PAH-PASMCs.

Original languageEnglish
Pages (from-to)309-327
Number of pages19
JournalCirculation research
Volume125
Issue number3
DOIs
Publication statusPublished - 2019 Jul 19

Keywords

  • cell proliferation
  • energy metabolism
  • hypertension
  • hypoxia-inducible factor 1
  • reactive oxygen species

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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