Hypoxic Pulmonary Vascular Smooth Muscle Cell Proliferation

Mizuno, Shiro; Toga, Hirohisa; Ishizaki, Takeshi

doi:10.5772/45979

Cited by 3 publications

(1 citation statement)

References 54 publications

(65 reference statements)

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“…The potential implication of HIF-1␣ in the pathogenesis of hypoxia-induced PH has been extensively debated during the past decade. A previous study (19) has reported that HIF-1␣ played an important role in hypoxia-induced cell proliferation in vitro. Using smooth muscle-specific conditional HIF-1␣ KO mice (HIF-1␣-SMM-Cre mice), Ball et al…”

Section: Discussionmentioning

confidence: 98%

Pyk2 aggravates hypoxia-induced pulmonary hypertension by activating HIF-1α

Fukai

Nakamura

Hoshino

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Pulmonary arterial hypertension (PAH) is a refractory disease characterized by uncontrolled vascular remodeling and elevated pulmonary arterial pressure. Although synthetic inhibitors of some tyrosine kinases have been used to treat PAH, their therapeutic efficacies and safeties remain controversial. Thus, the establishment of novel therapeutic targets based on the molecular pathogenesis underlying PAH is a clinically urgent issue. In the present study, we demonstrated that proline-rich tyrosine kinase 2 (Pyk2), a nonreceptor type protein tyrosine kinase, plays a crucial role in the pathogenesis of pulmonary hypertension (PH) using an animal model of hypoxia-induced PH. Resistance to hypoxia-induced PH was markedly higher in Pyk2-deficient mice than in wild-type mice. Pathological investigations revealed that medial thickening of the pulmonary arterioles, which is a characteristic of hypoxia-induced PH, was absent in Pyk2-deficient mice, suggesting that Pyk2 is involved in the hypoxia-induced aberrant proliferation of vascular smooth muscle cells in hypoxia-induced PH. In vitro experiments using human pulmonary smooth muscle cells showed that hypoxic stress increased the proliferation and migration of cells in a Pyk2-dependent manner. We also demonstrated that Pyk2 plays a crucial role in ROS generation during hypoxic stress and that this Pyk2-dependent generation of ROS is necessary for the activation of hypoxia-inducible factor-1α, a key molecule in the pathogenesis of hypoxia-induced PH. In summary, the results of the present study reveal that Pyk2 plays an important role in the pathogenesis of hypoxia-induced PH. Therefore, Pyk2 may represent a promising therapeutic target for PAH in a clinical setting.

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Section: Discussionmentioning

confidence: 98%

Pyk2 aggravates hypoxia-induced pulmonary hypertension by activating HIF-1α

Fukai

Nakamura

Hoshino

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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TIGAR reduces smooth muscle cell autophagy to prevent pulmonary hypertension

Yamanaka

Hoshino

Fukai

et al. 2020

American Journal of Physiology-Heart and Circulatory Physiology

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Background: Pulmonary arterial hypertension (PAH) is a refractory disease. Its prognosis remains poor; hence, establishment of novel therapeutic targets is urgent. TP53-induced glycolysis and apoptosis regulator (TIGAR) is a downstream target of p53, and exhibits functions inhibiting autophagy and reactive oxygen species (ROS). Recently, p53 was shown to suppress the PAH progression. Since inhibition of autophagy and ROS are known to improve PAH, we examined the effect of TIGAR on PAH progression. Methods: We compared pulmonary hypertension (PH) development between TIGAR-deficient knockout (KO) and wild type (WT) mice using a hypoxia-induced PH model. Human pulmonary artery smooth muscle cells (PASMCs) were used for in vitro experiments with small interfering RNA (siRNA) to investigate the possible molecular mechanisms. Results: From analysis of right ventricular pressure, right heart weight, and mortality rate, we concluded that the hypoxia-induced PH development was remarkably higher in TIGAR KO than in the WT mice. Pathological investigation revealed that medial thickening of the pulmonary arterioles and cell proliferation was increased in TIGAR KO mice. Autophagy and ROS activity was also increased in TIGAR KO mice. TIGAR knockdown by siRNA increased cell proliferation and migration, exacerbated autophagy, and increased ROS generation during hypoxia. Autophagy inhibition by chloroquine and ROS inhibition by N-acetylcysteine attenuated the proliferation and migration of PASMCs caused by TIGAR knockdown and hypoxia exposure. Conclusions: TIGAR suppressed the proliferation and migration of PASMCs via inhibiting autophagy and ROS, and therefore, improved hypoxia-induced PH. Thus, TIGAR might be a promising therapeutic target for PAH.

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Upregulation of microRNA-17-5p contributes to hypoxia-induced proliferation in human pulmonary artery smooth muscle cells through modulation of p21 and PTEN

Liu

Peng

et al. 2018

Respir Res

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BackgroundPulmonary arterial smooth muscle cell (PASMC) proliferation in response to hypoxia plays an important role in the vascular remodelling that occurs in hypoxic pulmonary hypertension. MicroRNAs (miRs) are emerging as important regulators in the progression of pulmonary hypertension. In this study, we investigated whether the expression of miR-17-5p is modulated by hypoxia and is involved in the hypoxia-induced proliferation of PASMCs.MethodsHuman PASMCs were cultured under hypoxic conditions. miR-17-5p expression was determined by real-time RT-PCR. A BrdU incorporation assay and time-lapse recording were utilized to determine cell proliferation and migration.ResultsPASMC proliferation was increased by moderate hypoxia (3% oxygen) but was reduced by severe hypoxia (0.1% oxygen) after 48 h. Moderate hypoxia induced miR-17-5p expression. Overexpression of miR-17-5p by transfection with miR-17-5p enhanced cell proliferation and migration in normoxia, whereas knockdown of miR-17-5p with anti-miR-17-5p inhibitors significantly reduced cell proliferation and migration. The expression of miR-17-5p target genes, specifically phosphatase and tensin homologue (PTEN) and cyclin-dependent kinase inhibitor 1 (p21WAF1/Cip1, p21), was reduced under moderate hypoxia in PASMCs. Under normoxia, overexpression of miR-17-5p in PASMCs reduced the expression of PTEN and p21.ConclusionOur data indicate that miR-17-5p might play a significant role in hypoxia-induced pulmonary vascular smooth muscle cell proliferation by regulating multiple gene targets, including PTEN and p21, and that miR-17-5p could be a novel therapeutic target for the management of hypoxia-induced PH.

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Hypoxic Pulmonary Vascular Smooth Muscle Cell Proliferation

Cited by 3 publications

References 54 publications

Pyk2 aggravates hypoxia-induced pulmonary hypertension by activating HIF-1α

Pyk2 aggravates hypoxia-induced pulmonary hypertension by activating HIF-1α

TIGAR reduces smooth muscle cell autophagy to prevent pulmonary hypertension

Upregulation of microRNA-17-5p contributes to hypoxia-induced proliferation in human pulmonary artery smooth muscle cells through modulation of p21 and PTEN

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