Adipose-derived regenerative cell therapy inhibits the progression of monocrotaline-induced pulmonary hypertension in rats.
OBJECTIVE
Functional and structural changes in pulmonary vasculature characterize pulmonary arterial hypertension (PAH) and the prognosis of advanced PAH remains poor despite progress in pharmacotherapy. Adipose-derived regenerative cells (ADRCs) promote cell regeneration at pathological sites and comprise a novel therapy for ailments of various organs. We investigated the effects of ADRC therapy in rat models of monocrotaline (MCT)-induced pulmonary hypertension (PH) and the underlying mechanisms.


METHODS
Rats were assigned to Control and MCT groups without and with (M/A) intravenous transfusion of seven million ADRCs on day 7. We echocardiographically evaluated pulmonary hypertension as pulmonary artery flow acceleration time (PAAT) and deceleration (PADc). Right ventricular (RV) systolic pressure was measured by catheterization on day 28 and then pathological changes in pulmonary vessels were assessed. We analyzed PAH-associated gene expression on day 14 using real-time RT-PCR.


RESULTS
Echocardiography and RV catheterization showed that ADRC therapy inhibited PH development (assessed as PAAT, PADc, and RV systolic pressure) at day 28 (MCT vs. M/A, P<0.05). Pulmonary vascular remodeling was also inhibited (vessel wall thickness: MCT vs. M/A, P<0.01). Messenger RNA levels of endothelin (ET) A and B receptors, ET-1 and transforming growth factor (TGF)-β increased in the lungs by MCT were suppressed by ADRCs (MCT vs. M/A, P<0.05).


CONCLUSIONS
The development of PH was inhibited by ADRCs through suppressing changes in the expression of genes associated with ET and TGF-β systems. We believe that ADRC therapy could serve as a novel strategy for treating PH.
Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Masamichi
M
Eguchi
Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Satoshi
S
Ikeda
Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Saburo
S
Kusumoto
Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Daisuke
D
Sato
Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Yuji
Y
Koide
Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Hiroaki
H
Kawano
Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. Electronic address: maemura@nagasaki-u.ac.jp.
Koji
K
Maemura
D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D018450:Disease Progression; D020869:Gene Expression Profiling; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy*; D008168:Lung / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D016686:Monocrotaline; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D044968:Regenerative Medicine; D033581:Stem Cell Transplantation; D016019:Survival Analysis; D066253:Vascular Remodeling; D015430:Weight Gain
D012333:RNA, Messenger; D016686:Monocrotaline
Adipose derived regenerative cell (ADRC); Endothelin-1; Pulmonary hypertension; Transforming growth factor beta