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Identification of celastramycin as a novel therapeutic agent for pulmonary arterial hypertension -high-throughput screening of 5,562 compounds-

Session Novel pharmacological targets in vascular disease

Speaker Ryo Kurosawa

Congress : ESC Congress 2019

  • Topic : basic science
  • Sub-topic : Hypertension, Pulmonary Hypertension
  • Session type : Advances in Science
  • FP Number : 55

Authors : R Kurosawa (Sendai,JP), K Satoh (Sendai,JP), N Kikuchi (Sendai,JP), T Satoh (Sendai,JP), J Omura (Sendai,JP), M Nogi (Sendai,JP), S Sunamura (Sendai,JP), T Ohtsuki (Sendai,JP), N Yaoita (Sendai,JP), M Abdul Hai Siddique (Sendai,JP), ME Al-Mamun (Sendai,JP), T Shimizu (Sendai,JP), H Shimokawa (Sendai,JP)

Authors:
R Kurosawa1 , K Satoh1 , N Kikuchi1 , T Satoh1 , J Omura1 , M Nogi1 , S Sunamura1 , T Ohtsuki1 , N Yaoita1 , M Abdul Hai Siddique1 , ME Al-Mamun1 , T Shimizu1 , H Shimokawa1 , 1Tohoku University Graduate School of Medicine, Cardiovascular Medicine - Sendai - Japan ,

Citation:

Background: 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 mitochondrial metabolism to a hyperproliferative state.  However, at present, since all the drugs in clinical use target pulmonary vascular dilatation, they may not be so effective for patients with advanced PAH.  Purposes: We aimed to discover a novel drug for PAH that inhibits PASMC proliferation.  Methods: In the first screening, we examined 5,562 compounds from our original library using high-throughput screening system to discover a compound that inhibits proliferation of PASMCs from PAH patients (PAH-PASMCs).  In the second screening, we performed concentration-dependent assays and counter assays with PAH-PASMCs and PASMCs from healthy donors.  We also performed apoptosis assays and mechanistic analysis for inflammation, reactive oxygen species (ROS), and mitochondrial function.  Results: 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 minimal effects on PASMCs from healthy donors.  Moreover, celastramycin inhibited proliferation with minimal increase in apoptosis and low rate of cell death.  Then, we synthesized 25 analogues of celastramycin, and finally selected the lead compound that significantly inhibited proliferation of PAH-PASMCs and reduced cytosolic ROS levels.  Mechanistic analysis demonstrated that celastramycin reduced the protein levels of hypoxia-inducible factor-1a, which was abnormally activated in PAH-PASMCs and impaired aerobic metabolism, and nuclear factor-?B, which induces pro-inflammatory signals, in PAH-PASMCs compared with vehicle controls, leading to reduced secretion of inflammatory cytokines.  Importantly, celastramycin treatment reduced the ROS levels in PAH-PASMCs with increased protein levels of NF-E2-related factor 2 (Nrf2), a master regulator of cellular response against oxidative stress.  Furthermore, celastramycin treatment improved mitochondrial energy metabolism with recovered mitochondrial network formation in PAH-PASMCs.  We also discovered that celastramycin-mediated effects on these transcriptional modulators could be regulated by zinc finger C3H1 domain-containing protein, which is a binding partner of celastramycin.  Finally, celastramycin treatment ameliorated pulmonary hypertension in three experimental animal models of PH in mice and rats, accompanied by reduced inflammatory changes in the lungs.  Conclusions: These results indicate that celastramycin ameliorates pulmonary hypertension through inhibition of excessive proliferation of PAH-PASMCs, for which its anti-inflammatory and beneficial effects on mitochondrial energy metabolism may be involved.  Thus, celastramycin could be a novel drug for PAH as it exerts anti-proliferative effects on PAH-PASMCs.

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