Pulmonary arterial hypertension (PAH) is a fatal disease characterized by excessive
vascular smooth muscle cells proliferation in small pulmonary arteries, leading to
elevation of pulmonary vascular resistance with consequent right ventricular (RV)
failure and death. Recently, emerging evidence has shown that leptin signaling is
involved in different cardiac pathologies; however, the role of leptin remains limited
in the setting of PAH. Thus, in this study, we tested the hypothesis of direct involvement
of leptin in the development of PAH. Our data show that leptin activity in plasma
and protein level in the lung were higher in hypoxia- and monocrotaline-induced PAH
models compared with control animals. Wild-type (WT) and C57BL/6J-Lepob (ob/ob) male mice were exposed to normobaric hypoxia (10% O2) or normoxia (21% O2). After 2 and 4 weeks of chronic hypoxia exposure, WT mice developed PAH as reflected
by the increased values of RV systolic pressure, RV hypertrophy index, the medial
wall thickness of pulmonary arterioles, and muscularization of pulmonary arterioles.
And, all these alterations were attenuated in ob/ob mice treated with hypoxia. Leptin could stimulate the proliferation of pulmonary
arterial smooth muscle cells (PASMCs) by activating extracellular signal–regulated
kinase (ERK), signal transducer and activator of transcription 3 (STAT3), and Akt
pathways. These data suggest that the leptin signaling pathway is crucial for the
development of PAH. Leptin activates ERK, STAT, and Akt pathways and subsequently
PASMCs proliferation, providing new mechanistic information about hypoxia-induced
PAH.
Abbreviations:
PAH (pulmonary arterial hypertension), PASMC (pulmonary arterial smooth muscle cells), MCT (monocrotaline), RVSP (right ventricular systolic pressure), RVHI (right ventricular hypertrophy index), SMCM (smooth muscle cell medium), FBS (fetal bovine serum), CFSE (5(6)-Carboxyfluorescein N-hydroxysuccinimidyl ester), MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), α-SMA (α-smooth muscle actin), vWF (von Willebrand factor)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: September 24, 2015
Accepted:
September 18,
2015
Received in revised form:
September 7,
2015
Received:
April 16,
2015
Footnotes
Jun Wang and Chen Wang are co-corresponding authors.
Identification
Copyright
© 2015 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
