Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension

Nawa, Nobutoshi; Ishida, Hidekazu; Katsuragi, Shinichi; Baden, Hiroki; Takahashi, Kyoko; Higeno, Ryota; Torigoe, Fumiko; Mihara, Seiko; Narita, Jun; Miura, Kouji; Nakamura, Kazufumi; Kogaki, Shigetoyo; Ozono, Keiichi

doi:10.1038/mtm.2016.44

Cited by 10 publications

(10 citation statements)

References 37 publications

(72 reference statements)

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“…Western blotting was performed as described previously, with some modifications [20]. Briefly, cells were lysed with RIPA Buffer (FUJIFILM Wako Pure Chemical Corporation) containing a protease inhibitor mixture (Roche Diagnostics, Basel, Switzerland).…”

Section: Methodsmentioning

confidence: 99%

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Elimination of protein aggregates prevents premature senescence in human trisomy 21 fibroblasts

et al. 2019

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Chromosome abnormalities induces profound alterations in gene expression, leading to various disease phenotypes. Recent studies on yeast and mammalian cells have demonstrated that aneuploidy exerts detrimental effects on organismal growth and development, regardless of the karyotype, suggesting that aneuploidy-associated stress plays an important role in disease pathogenesis. However, whether and how this effect alters cellular homeostasis and long-term features of human disease are not fully understood. Here, we aimed to investigate cellular stress responses in human trisomy syndromes, using fibroblasts and induced pluripotent stem cells (iPSCs). Dermal fibroblasts derived from patients with trisomy 21, 18 and 13 showed a severe impairment of cell proliferation and enhanced premature senescence. These phenomena were accompanied by perturbation of protein homeostasis, leading to the accumulation of protein aggregates. We found that treatment with sodium 4-phenylbutyrate (4-PBA), a chemical chaperone, decreased the protein aggregates in trisomy fibroblasts. Notably, 4-PBA treatment successfully prevented the progression of premature senescence in secondary fibroblasts derived from trisomy 21 iPSCs. Our study reveals aneuploidy-associated stress as a potential therapeutic target for human trisomies, including Down syndrome.

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Section: Methodsmentioning

confidence: 99%

“…Immunocytochemistry was performed as described previously, with some modifications [20]. Mitochondria were stained by exposing cells to MitoTracker Red CMXRos (100 nM, Thermo Fisher Scientific Inc.) for 15 minutes before fixation with 4% paraformaldehyde/phosphate-buffered saline (PBS).…”

Section: Methodsmentioning

confidence: 99%

Elimination of protein aggregates prevents premature senescence in human trisomy 21 fibroblasts

et al. 2019

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“…After ligation of the trachea, the lungs were fixed by immersion in 4% paraformaldehyde/10% buffered formalin overnight. They were then blocked and embedded in paraffin and cut into 5 μm thick sections 22 , 23 .…”

Section: Methodsmentioning

confidence: 99%

“…The pulmonary arteries were stained with Elastica Van Gieson stain and percent medial wall thickness was calculated in ten muscular arteries of resistant arteries (outer diameter of 50–200 μm) per lung, using the following formula: 100 × (external diameter – internal diameter)/external diameter 23 .…”

Section: Methodsmentioning

confidence: 99%

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Innovative therapeutic strategy using prostaglandin I2 agonist (ONO1301) combined with nano drug delivery system for pulmonary arterial hypertension

Kanaya

Miyagawa

Kawamura

et al. 2021

Sci Rep

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Clinical outcomes of pulmonary arterial hypertension (PAH) may be improved using targeted delivery system. We investigated the efficacy of ONO1301 (prostacyclin agonist) nanospheres (ONONS) in Sugen5416/hypoxia rat models of PAH. The rats were injected with saline (control) or ONONS (n = 10, each) on days 21 and 28, respectively. Hepatocyte growth factor (HGF)-expressing fibroblasts and inflammatory cytokines were measured. Cardiac performance was assessed and targeted delivery was monitored in vivo, using Texas red-labeled nanoparticles. Compared with control, HGF-expressing fibroblasts and HGF expression levels were significantly higher in the ONONS group, while the levels of interleukin-6, interleukin-1β, transforming growth factor-β, and platelet-derived growth factor were lower. Histological assessment revealed significant amelioration of the percent medial wall thickness in pulmonary vasculature of rats in the ONONS group. Rats in the ONONS group showed decreased proliferating cell nuclear antigen-positive smooth muscle cells and improved right ventricle pressure/left ventricle pressure. No difference was seen in the accumulation of Texas red-labeled nanoparticles in the brain, heart, liver, and spleen between PAH and normal rats. However, a significant area of nanoparticles was detected in the lungs of PAH rats. ONONS effectively ameliorated PAH, with selective delivery to the damaged lung.

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Metabolic Reprogramming of the Right Ventricle and Pulmonary Arteries in a Flow-Associated Pulmonary Arterial Hypertension Rat Model

Liu

Qin

et al. 2021

ACS Omega

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Pulmonary arterial hypertension (PAH) is a complex devastating disease relevant to remarkable metabolic dysregulation. Although various research studies on PAH from a metabolic perspective have been emerging, pathogenesis of PAH varies in different categories. Research on metabolic reprogramming in flow-associated PAH remains insufficient. An untargeted metabolomic profiling platform was used to evaluate the metabolic profile of pulmonary arteries (PAs) as well as the right ventricle (RV) in a flow-associated PAH rat model in the present work. A total of 79 PAs and 128 RV metabolites were significantly altered in PAH rats, among which 39 metabolites were assessed as shared dysregulated metabolites in PAs and the RV. Pathway analysis elucidated that, in PAs of PAH rats, pathways of phenylalanine, tyrosine, and tryptophan biosynthesis and linoleic acid metabolism were significantly altered, while in the RV, arginine biosynthesis and linoleic acid metabolism were altered dramatically. Further integrated analysis of shared dysregulated PA and RV metabolites demonstrated that the linoleic acid metabolism and the arachidonic acid (AA) metabolism were the key pathways involved in the pathogenesis of flow-associated PAH. Results obtained from the present work indicate that the PAH pathogenesis could be mediated by widespread metabolic reprogramming. In particular, the dysregulation of AA metabolism may considerably contribute to the development of high blood flow-associated PAH.

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Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension

Cited by 10 publications

References 37 publications

Elimination of protein aggregates prevents premature senescence in human trisomy 21 fibroblasts

Elimination of protein aggregates prevents premature senescence in human trisomy 21 fibroblasts

Innovative therapeutic strategy using prostaglandin I2 agonist (ONO1301) combined with nano drug delivery system for pulmonary arterial hypertension

Metabolic Reprogramming of the Right Ventricle and Pulmonary Arteries in a Flow-Associated Pulmonary Arterial Hypertension Rat Model

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