4-Phenylbutyric Acid Induces Protection against Pulmonary Arterial Hypertension in Rats.
BACKGROUND
Endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of various pulmonary diseases via the activation of the unfolded protein response. However, the role of ER stress in pulmonary arterial hypertension (PAH) remains unclear. The well-known chemical chaperone 4-phenylbutyric acid (4-PBA) inhibits ER stress signaling. We hypothesized that known chemical chaperones, including 4-PBA, would inhibit the activation of ER stress and prevent and/or reverse PAH.


RESULTS
Male Wistar rats were randomly divided into four groups: a normal control group (NORMAL group), a PAH group, and two PAH model plus 4-PBA treatment groups. The latter two groups included rats receiving 4-PBA by gavage each day as a preventive measure (the PRE group, with PBA starting on the day of PAH induction and continuing for 4 weeks) or as a reversal measure (the REV group, with PBA starting on the third week of PAH induction and continuing for 2 weeks). The PAH model was induced by intraperitoneally administering monocrotaline. The mean pulmonary artery pressure and mean right ventricular pressure were lower in the REV and PRE groups than in the NORMAL group. Furthermore, 4-PBA improved pulmonary arterial remodeling and suppressed the expression of ER stress indicators.


CONCLUSIONS
Our findings indicate that PAH induces ER stress and provokes pulmonary arterial and right ventricular remodeling. Additionally, we show that attenuation of ER stress has the potential to be an effective therapeutic strategy for protecting pulmonary arteries.
Department of General Practice, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011 P.R., China.|Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011 P.R., China.
Yun
Y
Wu
Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011 P.R., China.
Dilare
D
Adi
Department of Mechanism and Function, Xinjiang Medical University, Urumqi, 830011 P.R., China.
Mei
M
Long
Department of Pharmacy, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011 P.R., China.
Jie
J
Wang
Xinjiang Key Laboratory of Cardiovascular Disease Research, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011 P.R., China.
Fen
F
Liu
Xinjiang Key Laboratory of Cardiovascular Disease Research, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011 P.R., China.
Min-Tao
MT
Gai
Department of General Practice, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011 P.R., China.
Alidan
A
Aierken
Department of General Practice, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011 P.R., China.
Ming-Yuan
MY
Li
Department of General Practice, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011 P.R., China.
Qian
Q
Li
Department of General Practice, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011 P.R., China.
Lei-Qi
LQ
Wu
Xinjiang Key Laboratory of Cardiovascular Disease Research, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011 P.R., China.|Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011 P.R., China.
Yi-Tong
YT
Ma
Department of General Practice, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011 P.R., China.
Minawaer
M
Hujiaaihemaiti
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D016686:Monocrotaline; D010654:Phenylbutyrates / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D011897:Random Allocation; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
D000970:Antineoplastic Agents; D006360:Heat-Shock Proteins; D016686:Monocrotaline; D010654:Phenylbutyrates; D020011:Protective Agents; D019892:eIF-2 Kinase; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C075773:4-phenylbutyric acid