Salubrinal attenuates right ventricular hypertrophy and dysfunction in hypoxic pulmonary hypertension of rats.
The phosphorylation of eukaryotic translation initiation factor 2 alpha (p-eIF2α) is essential for cell survival during hypoxia. The aim of this study was to investigate whether salubrinal, an inhibitor of p-eIF2α dephosphorylation could attenuate pulmonary arterial hypertension (PAH) and right ventricular (RV) hypertrophy in rats exposed to hypobaric hypoxia. PAH of rats was induced by hypobaric hypoxia. Salubrinal supplemented was randomized in either a prevention or a reversal protocol. At the end of the follow-up point, we measured echocardiography, hemodynamics, hematoxylin-eosin and Masson's trichrome stainings. RNA-seq analysis is explored to identify changes in gene expression associated with hypobaric hypoxia with or without salubrinal. Compared with vehicle-treatment rats exposed to hypobaric hypoxia, salubrinal prevented and partly reversed the increase of the mean pulmonary artery pressure and RV hypertrophy. What's more, salubrinal reduced the percentage wall thickness (WT%) of pulmonary artery and RV collagen volume fraction (CVF) in both prevention and reversal protocols. We also found that salubrinal was capable of reducing endoplasmic reticulum stress and oxidative stress. The result of RNA-seq analysis revealed that chronic hypoxia stimulated the differential expression of a series of genes involved in cell cycle regulation and ventricular hypertrophy and so on. Some of these genes could be ameliorated by salubrinal. These results indicate that salubrinal could prevent and reverse well-established RV remodeling, and restore the genes and pathways altered in the right ventricles of rats exposed to hypobaric hypoxia.
Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China; School of Medicine, Nankai University, Tianjin 300071, China.
Yun-Yun
YY
He
Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China.
Chun-Lei
CL
Liu
Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China.
Xin
X
Li
Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China.
Rui-Jun
RJ
Li
Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: wangll63@126.com.
Li-Li
LL
Wang
Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China. Electronic address: hekl301@aliyun.com.
Kun-Lun
KL
He
D000818:Animals; D002934:Cinnamates / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D000860:Hypoxia; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D018497:Ventricular Dysfunction, Right / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000187:drug effects / Q000235:genetics
D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; C496827:salubrinal; D013890:Thiourea
Pulmonary hypertension; Right ventricular hypertrophy; Salubrinal