mTOR Signaling in Pulmonary Vascular Disease: Pathogenic Role and Therapeutic Target

Babicheva, Aleksandra; Makino, Ayako; Yuan, Jason X.‐J.

doi:10.3390/ijms22042144

Cited by 41 publications

(30 citation statements)

References 198 publications

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“…The PI3K/AKT/mTOR signaling cascade is a major signaling pathway involved in cell proliferation and protein synthesis in a variety of cell types including cancer cells and PASMCs ( Goncharov et al, 2014 ; Sahoo et al, 2016 ; Meng et al, 2017 ; Babicheva et al, 2021 ). Our lab and other investigators have reported that the PI3K/AKT1/mTORC1/C2 pathways are involved in the development and progression of experimental PH in mice ( Tang et al, 2015 , 2018b ; Goncharova et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

“…The mTOR complex 1 (mTORC1) and mTORC2 play important roles in the regulation of cell proliferation and protein expression, while both complexes are involved in the development and progression of PH ( Houssaini et al, 2013 , 2016 ; Goncharov et al, 2014 ; Lee et al, 2016 ; Guo et al, 2019 ; Goncharova et al, 2020 ; Babicheva et al, 2021 ). PASMCs in the normal PA exhibit a differentiated, quiescent, and contractile phenotype.…”

Section: Resultsmentioning

confidence: 99%

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Upregulation of Calcium Homeostasis Modulators in Contractile-To-Proliferative Phenotypical Transition of Pulmonary Arterial Smooth Muscle Cells

Rodriguez¹,

Chen²,

Jain³

et al. 2021

Front. Physiol.

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Excessive pulmonary artery (PA) smooth muscle cell (PASMC) proliferation and migration are implicated in the development of pathogenic pulmonary vascular remodeling characterized by concentric arterial wall thickening and arteriole muscularization in patients with pulmonary arterial hypertension (PAH). Pulmonary artery smooth muscle cell contractile-to-proliferative phenotypical transition is a process that promotes pulmonary vascular remodeling. A rise in cytosolic Ca2+ concentration [(Ca2+)cyt] in PASMCs is a trigger for pulmonary vasoconstriction and a stimulus for pulmonary vascular remodeling. Here, we report that the calcium homeostasis modulator (CALHM), a Ca2+ (and ATP) channel that is allosterically regulated by voltage and extracellular Ca2+, is upregulated during the PASMC contractile-to-proliferative phenotypical transition. Protein expression of CALHM1/2 in primary cultured PASMCs in media containing serum and growth factors (proliferative PASMC) was significantly greater than in freshly isolated PA (contractile PASMC) from the same rat. Upregulated CALHM1/2 in proliferative PASMCs were associated with an increased ratio of pAKT/AKT and pmTOR/mTOR and an increased expression of the cell proliferation marker PCNA, whereas serum starvation and rapamycin significantly downregulated CALHM1/2. Furthermore, CALHM1/2 were upregulated in freshly isolated PA from rats with monocrotaline (MCT)-induced PH and in primary cultured PASMC from patients with PAH in comparison to normal controls. Intraperitoneal injection of CGP 37157 (0.6 mg/kg, q8H), a non-selective blocker of CALHM channels, partially reversed established experimental PH. These data suggest that CALHM upregulation is involved in PASMC contractile-to-proliferative phenotypical transition. Ca2+ influx through upregulated CALHM1/2 may play an important role in the transition of sustained vasoconstriction to excessive vascular remodeling in PAH or precapillary PH. Calcium homeostasis modulator could potentially be a target to develop novel therapies for PAH.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Upregulation of Calcium Homeostasis Modulators in Contractile-To-Proliferative Phenotypical Transition of Pulmonary Arterial Smooth Muscle Cells

Rodriguez¹,

Chen²,

Jain³

et al. 2021

Front. Physiol.

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“…Houssaini et al have reported that the proliferation of PASMCs derived from MCT-induced PAH rats was suppressed by rapamycin [ 22 ], an allosteric inhibitor of mTOR complex 1 [ 18 ]. Notably, restoring the mTOR pathway by upregulating phosphatase and tensin homolog, a regulator of mTOR [ 20 ], induces apoptosis in PASMCs [ 38 ]. In the present study, 10 μM H-1337M1 suppressed the activation of mTOR and the cell viability of hPASMCs at a level similar to that of LY294002, although the effects of 1 and 10 μM H-1337 and 1 μM H-1337 M1 on mTOR were moderate.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, the mammalian target of rapamycin (mTOR) pathway has also been shown to be associated with PAH development. The activated mTOR pathway induces the proliferation of SMCs [ 18 , 19 ] and is associated with the development of vascular remodeling in PAH [ 20 ]. Moreover, the mTOR pathway is activated in experimental PAH animal models induced by hypoxia, MCT, and Su5416/hypoxia (Su/Hx) rat models, which are associated with the development of pulmonary vascular remodeling and right ventricle (RV) remodeling and dysfunction [ 21 , 22 , 23 ] Thus, activation of the ROCK and Akt/mTOR pathways plays important roles in PAH development, and inhibition of these pathways may be a new strategy for treating PAH.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, H-1337 and its metabolite H-1337M1 were found to have inhibitory activities on Akt in a preliminary experiment. Although inhibition of ROCK or Akt pathways has been shown to suppress the development of PAH [ 20 , 26 ], the effects of inhibition of both ROCK and Akt pathways on PAH have not been investigated. Thus, we hypothesized that H-1337 may exert antiproliferative effects on vascular lesion cells and pulmonary vasodilative effects via inhibition of both ROCK and Akt signaling.…”

Section: Introductionmentioning

confidence: 99%

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The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats

Shoji

Yoshida

Jujo

et al. 2021

Cells

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Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure and right heart failure. Selective pulmonary vasodilators have improved the prognosis of PAH; however, they are not able to reverse pulmonary vascular remodeling. Therefore, a search for new treatment agents is required. H-1337 is an isoquinoline-sulfonamide compound that inhibits multiple serine/threonine kinases, including Rho-associated protein kinase (ROCK) and mammalian target of rapamycin (mTOR). Here, we investigated the effects of H-1337 on pulmonary hypertension and remodeling in the pulmonary vasculature and right ventricle in experimental PAH induced by SU5416 and hypoxia exposure. H-1337 and H-1337M1 exerted inhibitory effects on ROCK and Akt. H-1337 inhibited the phosphorylation of myosin light chain and mTOR and suppressed the proliferation of smooth muscle cells in vitro. H-1337 treatment also suppressed the phosphorylation of myosin light chain and mTOR in the pulmonary vasculature and decreased right ventricular systolic pressure and the extent of occlusive pulmonary vascular lesions. Furthermore, H-1337 suppressed aggravation of right ventricle hypertrophy. In conclusion, our data demonstrated that inhibition of ROCK and mTOR pathways with H-1337 suppressed the progression of pulmonary vascular remodeling, pulmonary hypertension, and right ventricular remodeling.

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Framework Nucleic Acids Enabled Pulmonary Artery Endothelial Cell Growth Inhibition by Targeting microRNA‐152

You

Huang

et al. 2022

ChemBioChem

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Pulmonary artery vascular endothelial dysfunction plays a pivotal role in the occurrence and progression of pulmonary vascular remodeling (PVR). To address this, aberrantly expressed non‐coding microRNAs (miRNAs) are excellent therapeutic targets in human pulmonary artery endothelial cells (HPAECs). Here, we discovered and validated the overexpression of miRNA‐152 in HPAECs under hypoxia and its role in endothelial cell dysfunction. We constructed a framework nucleic acid nanostructure that harbors six protruding single‐stranded DNA segments that can fully hybridize with miRNA‐152 (DNT‐152). DNT‐152 was efficiently taken up by HPAECs with increasing time and concentration; it markedly induced apoptosis, and inhibited HPAEC growth under hypoxic conditions. Mechanistically, DNT‐152 silenced miRNA‐152 expression and upregulated its target gene Meox2, which subsequently inhibited the AKT/mTOR signaling pathway. These results indicate that miRNA‐152 in HPAECs may be an excellent therapeutic target against PVR, and that framework nucleic acids with carefully designed sequences are promising nanomedicines for noncancerous cells and diseases.

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mTOR Signaling in Pulmonary Vascular Disease: Pathogenic Role and Therapeutic Target

Cited by 41 publications

References 198 publications

Upregulation of Calcium Homeostasis Modulators in Contractile-To-Proliferative Phenotypical Transition of Pulmonary Arterial Smooth Muscle Cells

Upregulation of Calcium Homeostasis Modulators in Contractile-To-Proliferative Phenotypical Transition of Pulmonary Arterial Smooth Muscle Cells

The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats

Framework Nucleic Acids Enabled Pulmonary Artery Endothelial Cell Growth Inhibition by Targeting microRNA‐152

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