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A Critical Role of the mTOR/eIF2α Pathway in Hypoxia-Induced Pulmonary Hypertension.

Wang AP, Li XH, Yang YM, Li WQ, Zhang W, Hu CP, Zhang Z, Li YJ - PLoS ONE (2015)

Bottom Line: The expression and activation of eIF2α, mTOR and c-myc were analyzed.In hypoxia-induced PASMCs, rapamycin and knockdown of mTOR and eIF2α by siRNA significantly abolished proliferation and increased c-myc expression.These results suggest a critical role of the mTOR/eIF2αpathway in hypoxic vascular remodeling and PASMCs proliferation of HPH.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China; Department of Anatomy, School of Medicine, University of South China, Hengyang, 421001, China.

ABSTRACT
Enhanced proliferation of pulmonary arterial vascular smooth muscle cells (PASMCs) is a key pathological component of vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Mammalian targeting of rapamycin (mTOR) signaling has been shown to play a role in protein translation and participate in the progression of pulmonary hypertension. Eukaryotic translation initiation factor-2α (eIF2α) is a key factor in regulation of cell growth and cell cycle, but its role in mTOR signaling and PASMCs proliferation remains unknown. Pulmonary hypertension (PH) rat model was established by hypoxia. Rapamycin was used to treat rats as an mTOR inhibitor. Proliferation of primarily cultured rat PASMCs was induced by hypoxia, rapamycin and siRNA of mTOR and eIF2α were used in loss-of-function studies. The expression and activation of eIF2α, mTOR and c-myc were analyzed. Results showed that mTOR/eIF2α signaling was significantly activated in pulmonary arteries from hypoxia exposed rats and PASMCs cultured under hypoxia condition. Treatment with mTOR inhibitor for 21 days attenuated vascular remodeling, suppressed mTOR and eIF2α activation, inhibited c-myc expression in HPH rats. In hypoxia-induced PASMCs, rapamycin and knockdown of mTOR and eIF2α by siRNA significantly abolished proliferation and increased c-myc expression. These results suggest a critical role of the mTOR/eIF2αpathway in hypoxic vascular remodeling and PASMCs proliferation of HPH.

No MeSH data available.


Related in: MedlinePlus

Effect of rapamycin on hemodynamic changes and vascular remodeling in HPH rats.(A) Right ventricle systolic pressure (RVSP). (B) Mean pulmonary artery pressure (mPAP). (C) Statistical graph analysis of pulmonary arterial media wall thickness (WT). (D) Hematoxylin-eosin staining in small PAs. Data are means ± S.E.M. n = 8. RAPA: rapamycin. **P<0.01 vs. control; ***P<0.001 vs. control; ##P<0.05 vs. hypoxia.
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pone.0130806.g003: Effect of rapamycin on hemodynamic changes and vascular remodeling in HPH rats.(A) Right ventricle systolic pressure (RVSP). (B) Mean pulmonary artery pressure (mPAP). (C) Statistical graph analysis of pulmonary arterial media wall thickness (WT). (D) Hematoxylin-eosin staining in small PAs. Data are means ± S.E.M. n = 8. RAPA: rapamycin. **P<0.01 vs. control; ***P<0.001 vs. control; ##P<0.05 vs. hypoxia.

Mentions: In keeping with a previous study [26], three weeks of exposure to hypoxia induced pulmonary hypertension in rats, as demonstrated by a significant elevation in RVSP and mPAP compared with the control rats (Fig 3A and 3B). Hypoxia also significantly induced hyperplasia of pulmonary arteries, compared with controls (Fig 3C and 3D). The elevation in RVSP and mPAP were decreased by mTOR inhibitor rapamycin (Fig 3A and 3B). Rapamycin treatment also attenuated hyperplasia in the vascular media of small pulmonary arteries (Fig 3C and 3D). Treatment with rapamycin also reversed hypoxia-induced PASMCs proliferation (Fig 5G and 5H). Taken together, these results showed that the mTOR inhibitor rapamycin attenuates vascular remodeling of HPH, most likely through inhibition of PASMCs proliferation.


A Critical Role of the mTOR/eIF2α Pathway in Hypoxia-Induced Pulmonary Hypertension.

Wang AP, Li XH, Yang YM, Li WQ, Zhang W, Hu CP, Zhang Z, Li YJ - PLoS ONE (2015)

Effect of rapamycin on hemodynamic changes and vascular remodeling in HPH rats.(A) Right ventricle systolic pressure (RVSP). (B) Mean pulmonary artery pressure (mPAP). (C) Statistical graph analysis of pulmonary arterial media wall thickness (WT). (D) Hematoxylin-eosin staining in small PAs. Data are means ± S.E.M. n = 8. RAPA: rapamycin. **P<0.01 vs. control; ***P<0.001 vs. control; ##P<0.05 vs. hypoxia.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4487252&req=5

pone.0130806.g003: Effect of rapamycin on hemodynamic changes and vascular remodeling in HPH rats.(A) Right ventricle systolic pressure (RVSP). (B) Mean pulmonary artery pressure (mPAP). (C) Statistical graph analysis of pulmonary arterial media wall thickness (WT). (D) Hematoxylin-eosin staining in small PAs. Data are means ± S.E.M. n = 8. RAPA: rapamycin. **P<0.01 vs. control; ***P<0.001 vs. control; ##P<0.05 vs. hypoxia.
Mentions: In keeping with a previous study [26], three weeks of exposure to hypoxia induced pulmonary hypertension in rats, as demonstrated by a significant elevation in RVSP and mPAP compared with the control rats (Fig 3A and 3B). Hypoxia also significantly induced hyperplasia of pulmonary arteries, compared with controls (Fig 3C and 3D). The elevation in RVSP and mPAP were decreased by mTOR inhibitor rapamycin (Fig 3A and 3B). Rapamycin treatment also attenuated hyperplasia in the vascular media of small pulmonary arteries (Fig 3C and 3D). Treatment with rapamycin also reversed hypoxia-induced PASMCs proliferation (Fig 5G and 5H). Taken together, these results showed that the mTOR inhibitor rapamycin attenuates vascular remodeling of HPH, most likely through inhibition of PASMCs proliferation.

Bottom Line: The expression and activation of eIF2α, mTOR and c-myc were analyzed.In hypoxia-induced PASMCs, rapamycin and knockdown of mTOR and eIF2α by siRNA significantly abolished proliferation and increased c-myc expression.These results suggest a critical role of the mTOR/eIF2αpathway in hypoxic vascular remodeling and PASMCs proliferation of HPH.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China; Department of Anatomy, School of Medicine, University of South China, Hengyang, 421001, China.

ABSTRACT
Enhanced proliferation of pulmonary arterial vascular smooth muscle cells (PASMCs) is a key pathological component of vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Mammalian targeting of rapamycin (mTOR) signaling has been shown to play a role in protein translation and participate in the progression of pulmonary hypertension. Eukaryotic translation initiation factor-2α (eIF2α) is a key factor in regulation of cell growth and cell cycle, but its role in mTOR signaling and PASMCs proliferation remains unknown. Pulmonary hypertension (PH) rat model was established by hypoxia. Rapamycin was used to treat rats as an mTOR inhibitor. Proliferation of primarily cultured rat PASMCs was induced by hypoxia, rapamycin and siRNA of mTOR and eIF2α were used in loss-of-function studies. The expression and activation of eIF2α, mTOR and c-myc were analyzed. Results showed that mTOR/eIF2α signaling was significantly activated in pulmonary arteries from hypoxia exposed rats and PASMCs cultured under hypoxia condition. Treatment with mTOR inhibitor for 21 days attenuated vascular remodeling, suppressed mTOR and eIF2α activation, inhibited c-myc expression in HPH rats. In hypoxia-induced PASMCs, rapamycin and knockdown of mTOR and eIF2α by siRNA significantly abolished proliferation and increased c-myc expression. These results suggest a critical role of the mTOR/eIF2αpathway in hypoxic vascular remodeling and PASMCs proliferation of HPH.

No MeSH data available.


Related in: MedlinePlus