Role of smooth muscle cell p53 in pulmonary arterial hypertension

Takayuki Wakasugi, Ippei Shimizu, Yohko Yoshida, Yuka Hayashi, Ryutaro Ikegami, Masayoshi Suda, Goro Katsuumi, Masaaki Nakao, Makoto Hoyano, Takeshi Kashimura, Kazufumi Nakamura, Hiroshi Itoh, Takashi Nojiri, Tomoyoshi Soga, Tohru Minamino

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Abstract

Pulmonary arterial hypertension (PAH) is characterized by remodeling and narrowing of the pulmonary arteries, which lead to elevation of right ventricular pressure, heart failure, and death. Proliferation of pulmonary artery smooth muscle cells (PASMCs) is thought to be central to the pathogenesis of PAH, although the underlying mechanisms are still being explored. The protein p53 is involved in cell cycle coordination, DNA repair, apoptosis, and cellular senescence, but its role in pulmonary hypertension (PH) is not fully known. We developed a mouse model of hypoxia-induced pulmonary hypertension (PH) and found significant reduction of p53 expression in the lungs. Our in vitro experiments with metabolomic analyses and the Seahorse XF extracellular flux analyzer indicated that suppression of p53 expression in PASMCs led to upregulation of glycolysis and downregulation of mitochondrial respiration, suggesting a proliferative phenotype resembling that of cancer cells. It was previously shown that systemic genetic depletion of p53 in a murine PH model led to more severe lung manifestations. Lack of information about the role of cell-specific p53 signaling promoted us to investigate it in our mouse PH model with the inducible Cre-loxP system. We generated a mouse model with SMC-specific gain or loss of p53 function by crossing Myh11-Cre/ERT2 mice with floxed Mdm4 mice or floxed Trp53 mice. After these animals were exposed to hypoxia for 4 weeks, we conducted hemodynamic and echocardiographic studies. Surprisingly, the severity of PH was similar in both groups of mice and there were no differences between the genotypes. Our findings in these mice indicate that activation or suppression of p53 signaling in SMCs has a minor role in the pathogenesis of PH and suggest that p53 signaling in other cells (endothelial cells, immune cells, or fibroblasts) may be involved in the progression of this condition.

Original languageEnglish
Article numbere0212889
JournalPloS one
Volume14
Issue number2
DOIs
Publication statusPublished - Feb 1 2019

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Pulmonary Hypertension
smooth muscle
myocytes
hypertension
Smooth Muscle Myocytes
Muscle
lungs
Cells
mice
Pulmonary Artery
pulmonary artery
Endothelial cells
Hemodynamics
Fibroblasts
Animals
Repair
Chemical activation
Apoptosis
hypoxia
Fluxes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Wakasugi, T., Shimizu, I., Yoshida, Y., Hayashi, Y., Ikegami, R., Suda, M., ... Minamino, T. (2019). Role of smooth muscle cell p53 in pulmonary arterial hypertension. PloS one, 14(2), [e0212889]. https://doi.org/10.1371/journal.pone.0212889

Role of smooth muscle cell p53 in pulmonary arterial hypertension. / Wakasugi, Takayuki; Shimizu, Ippei; Yoshida, Yohko; Hayashi, Yuka; Ikegami, Ryutaro; Suda, Masayoshi; Katsuumi, Goro; Nakao, Masaaki; Hoyano, Makoto; Kashimura, Takeshi; Nakamura, Kazufumi; Itoh, Hiroshi; Nojiri, Takashi; Soga, Tomoyoshi; Minamino, Tohru.

In: PloS one, Vol. 14, No. 2, e0212889, 01.02.2019.

Research output: Contribution to journalArticle

Wakasugi, T, Shimizu, I, Yoshida, Y, Hayashi, Y, Ikegami, R, Suda, M, Katsuumi, G, Nakao, M, Hoyano, M, Kashimura, T, Nakamura, K, Itoh, H, Nojiri, T, Soga, T & Minamino, T 2019, 'Role of smooth muscle cell p53 in pulmonary arterial hypertension', PloS one, vol. 14, no. 2, e0212889. https://doi.org/10.1371/journal.pone.0212889
Wakasugi T, Shimizu I, Yoshida Y, Hayashi Y, Ikegami R, Suda M et al. Role of smooth muscle cell p53 in pulmonary arterial hypertension. PloS one. 2019 Feb 1;14(2). e0212889. https://doi.org/10.1371/journal.pone.0212889
Wakasugi, Takayuki ; Shimizu, Ippei ; Yoshida, Yohko ; Hayashi, Yuka ; Ikegami, Ryutaro ; Suda, Masayoshi ; Katsuumi, Goro ; Nakao, Masaaki ; Hoyano, Makoto ; Kashimura, Takeshi ; Nakamura, Kazufumi ; Itoh, Hiroshi ; Nojiri, Takashi ; Soga, Tomoyoshi ; Minamino, Tohru. / Role of smooth muscle cell p53 in pulmonary arterial hypertension. In: PloS one. 2019 ; Vol. 14, No. 2.
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