PMID- 34836745
OWN - NLM
STAT- MEDLINE
DCOM- 20220125
LR  - 20220125
IS  - 1618-095X (Electronic)
IS  - 0944-7113 (Linking)
VI  - 96
DP  - 2022 Feb
TI  - Osthole alleviates pulmonary vascular remodeling by modulating microRNA-22-3p 
      mediated lipid metabolic reprogramming.
PG  - 153840
LID - S0944-7113(21)00381-0 [pii]
LID - 10.1016/j.phymed.2021.153840 [doi]
AB  - BACKGROUND: Pulmonary vascular remodeling is the key pathological feature of 
      pulmonary arterial hypertension (PAH) characterized by a pattern of lipid-related 
      insulin resistance(IR), hormonal derangements and metabolic reprogramming. Our 
      previous studies have demonstrated osthole as natural coumarin compound derived 
      from traditional Chinese medicine is a promising agent for the treatment of 
      pulmonary vascular remodeling in PAH. PURPOSE: The present study sought to 
      delineate lipid metabolic modulatory mechanism of osthole against pulmonary 
      vascular remodeling by employing an interdisciplinary strategy. METHODS: Rat 
      model with PAH induced with MCT and PASMCs proliferation model induced with 
      PDGF-BB were established in this study. Serum and lung tissues were used to 
      lipid-related IR, hormone related indexes, pulmonary vascular remodeling 
      analysis. Then, lipid metabolic gene, key enzymes, metabolites and cell 
      proliferation indexes were examined to investigate metabolic regulatory mechanism 
      in vivo and vitro model of PAH. RESULTS: Osthole significantly showed improvement 
      of lipid-related IR and hormone dysregulation in rats with PAH evidenced by 
      elevating testosterone, androgen receptor and cyclic guanosine monophosphate 
      (cGMP), inhibiting phosphodiesterase-5(PDE-5), modulating lipid-related IR 
      indexes total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), 
      triglyceride (TG)/HDL-C ratio. Additionally, osthole limited key metabolic gene 
      and enzymes to inhibit accumulation of decadienyl-l-carnitine in lipid 
      metabolism, thus to promote oxidative phosphorylation and ATP production through 
      inhibition of miRNA-22-3p, fatty acid translocase (CD36), fatty acid synthase 
      (FAS), phospholipase A2 (PLA2), carnitine palmitoyltransferase 1A (CPT1A), 
      hexokinase 2 (HK2), activation of metabolic switch isocitrate dehydrogenase 3alpha 
      (IDH3alpha), NADH dehydrogenase 1 (ND1). We found for the first time miRNA-22-3p 
      modulated PASMCs proliferation and vascular remodeling by regulating lipid 
      metabolism reprogramming. Those modifications uncovered therapeutic mechanism of 
      osthole against pulmonary vascular remodeling. CONCLUSION: Our findings revealed 
      the function of miRNA-22-3p in PASMCs and demonstrated a novel mechanism that 
      miRNA-22-3p as a regulator can be targeted by osthole to greatly restore 
      dysregulated lipid metabolism thus to alleviate pulmonary vascular remodeling in 
      PAH, which provides novel insight into the potential therapeutic target for PAH, 
      further highlights the development potential of osthole derived new drug against 
      PAH.
CI  - Copyright (c) 2021. Published by Elsevier GmbH.
FAU - Niu, Zheng
AU  - Niu Z
AD  - Department of Medicinal Chemistry and Natural Medicine Chemistry, Department of 
      Pharmacognosy, College of Pharmacy, Harbin Medical University, Harbin 150081, 
      China.
FAU - Fu, Min
AU  - Fu M
AD  - Department of Medicinal Chemistry and Natural Medicine Chemistry, Department of 
      Pharmacognosy, College of Pharmacy, Harbin Medical University, Harbin 150081, 
      China.
FAU - Li, Yuan
AU  - Li Y
AD  - Department of Medicinal Chemistry and Natural Medicine Chemistry, Department of 
      Pharmacognosy, College of Pharmacy, Harbin Medical University, Harbin 150081, 
      China.
FAU - Ren, Huanhuan
AU  - Ren H
AD  - Department of Medicinal Chemistry and Natural Medicine Chemistry, Department of 
      Pharmacognosy, College of Pharmacy, Harbin Medical University, Harbin 150081, 
      China.
FAU - Zhang, Xuanyu
AU  - Zhang X
AD  - Department of Medicinal Chemistry and Natural Medicine Chemistry, Department of 
      Pharmacognosy, College of Pharmacy, Harbin Medical University, Harbin 150081, 
      China.
FAU - Yao, Li
AU  - Yao L
AD  - Department of Medicinal Chemistry and Natural Medicine Chemistry, Department of 
      Pharmacognosy, College of Pharmacy, Harbin Medical University, Harbin 150081, 
      China; State-Province Key Laboratory of Biomedicine-Pharmaceutics of China, 
      Harbin Medical University, Harbin 150081, China. Electronic address: 
      yaol@hrbmu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20211106
PL  - Germany
TA  - Phytomedicine
JT  - Phytomedicine : international journal of phytotherapy and phytopharmacology
JID - 9438794
RN  - 0 (Coumarins)
RN  - 0 (Lipids)
RN  - 0 (MIRN22 microRNA, rat)
RN  - 0 (MicroRNAs)
RN  - XH1TI1759C (osthol)
SB  - IM
MH  - Animals
MH  - Cell Proliferation
MH  - Coumarins/pharmacology
MH  - Disease Models, Animal
MH  - Lipids
MH  - *MicroRNAs/genetics
MH  - Myocytes, Smooth Muscle
MH  - Pulmonary Artery
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - *Vascular Remodeling
OTO - NOTNLM
OT  - lipid metabolism
OT  - metabolic reprogramming
OT  - miRNA-22-3p
OT  - osthole
OT  - pulmonary arterial hypertension
EDAT- 2021/11/28 06:00
MHDA- 2022/01/27 06:00
CRDT- 2021/11/27 05:29
PHST- 2021/05/14 00:00 [received]
PHST- 2021/09/02 00:00 [revised]
PHST- 2021/10/27 00:00 [accepted]
PHST- 2021/11/28 06:00 [pubmed]
PHST- 2022/01/27 06:00 [medline]
PHST- 2021/11/27 05:29 [entrez]
AID - S0944-7113(21)00381-0 [pii]
AID - 10.1016/j.phymed.2021.153840 [doi]
PST - ppublish
SO  - Phytomedicine. 2022 Feb;96:153840. doi: 10.1016/j.phymed.2021.153840. Epub 2021 
      Nov 6.