Unique wreath-like smooth muscle proliferation of the pulmonary vasculature in pulmonary veno-occlusive disease versus pulmonary arterial hypertension

Lai, Ying‐Ju; Chen, Po-Ru; Huang, Yen‐Lin; Hsu, Hsao‐Hsun

doi:10.1016/j.jfma.2019.05.019

Cited by 5 publications

(3 citation statements)

References 30 publications

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“…48 Another report, however, demonstrates similar GCN2 protein levels in IPAH and control lungs. 49 Our study here shows no marked difference in GCN2 expression, both mRNA and protein levels, in whole lung tissues as well as pulmonary vascular ECs between IPAH patient lungs and control lungs. Furthermore, our study provides unequivocal evidence of extensive GCN2 phosphorylation in pulmonary vascular lesions of IPAH patients, especially in vascular ECs.…”

Section: Discussioncontrasting

confidence: 46%

The Unexpected Role of GCN2 Kinase Activation in Mediating Pulmonary Arterial Hypertension

Zhu,

Dai,

Dai

et al. 2023

Preprint

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Background: Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and remodeling that result in right heart hypertrophy and failure. Published studies show that recessive mutations of EIF2AK4 gene (encoding GCN2, General control nonderepressibe 2 kinase) are linked to heritable pulmonary veno-occlusive disease (PVOD) in patients and EIF2AK4 mutations were also found in PAH patients although very rare. However, the role of GCN2 kinase in the pathogenesis of PAH remains unclear. Methods: Eif2ak4-/- mice with genetic disruption of the kinase domain and GCN2 kinase inhibitor A-92 were employed in animal models of PH including chronic hypoxia-exposed mice and monocrotaline-challenged rats. Human lung endothelial cells (HLMVECs) were used for mechanistic studies. Endothelium-targeted nanoparticles were employed to deliver plasmid DNA to adult mice to knockout Eif2ak4 or overexpress Endothelin-1 (Edn1) selectively in ECs. Results: Here we show that loss of GCN2 induced neither spontaneous PVOD nor PH in Eif2ak4-/- mice but inhibited hypoxia-induced PH evident by reduced right ventricular systolic pressure, right ventricle hypertrophy and pulmonary vascular remodeling. RNA sequencing analysis suggested Edn1 as the downstream target of GCN2. In cultured HLMVECs, GCN2 was phosphorylated and activated in response to hypoxia, mediating hypoxia-induced Edn1 expression via HIF-2?. Restored Edn1 expression in ECs in Gcn2-deficient mice reversed the reduced phenotype of hypoxia-induced PH. Furthermore, loss of endothelial Eif2ak4 in mice attenuated hypoxia-induced PH. Monocrotaline-induced PH and pulmonary vascular remodeling in rats were inhibited by GCN2 inhibitor A-92 treatment. The clinical relevance of the observation was validated by GCN2 hyperphosphorylation indicative of activation in ECs of pulmonary vascular lesions of PAH patients. Conclusion: These studies demonstrate that GCN2 activation by hypoxia mediates pulmonary vascular remodeling and PAH through Edn1. Thus, targeting GCN2 signaling is a promising therapeutic strategy for treatment of PAH in patients without EIF2AK4 loss of function mutations.

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Section: Discussioncontrasting

confidence: 46%

The Unexpected Role of GCN2 Kinase Activation in Mediating Pulmonary Arterial Hypertension

Zhu,

Dai,

Dai

et al. 2023

Preprint

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“…To evaluate the degree of fibrosis, tissue sections from lungs were stained with Masson trichrome according to the manufacturer's protocol (Bio-Optica, Milan, Italy), as previously described [60].…”

Section: Masson's Trichrome Stainingmentioning

confidence: 99%

The protective role of Prolyl oligopeptidase (POP) inhibition in acute lung injury induced by intestinal ischemia-reperfusion

et al. 2021

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Intestinal ischemia-reperfusion (II/R) develops when the blood flow to the intestines decreases, followed by the reestablishment of the blood supply to the ischemic tissue, resulting in intestinal mucosal barrier dysfunction, with consequent severe local and systemic inflammation. Acute lung injury (ALI) represents the most serious complication after II/R. KYP-2047 is a selective inhibitor of prolyl oligopeptidase (POP), a serine protease involved in the release of pro-angiogenic and inflammatory molecules. The aim of the present study is to assess the effects of POP-inhibition mediated by KYP-2047 treatment in the pathophysiology of ALI following II/R. An in vivo model of II/R was performed and mice were subjected to KYP-2047 treatment (intraperitoneal, 1, 2.5 and 5 mg/ kg). Histological analysis, Masson's trichrome staining, immunohistochemical, immunofluorescence, biochemical and western blots analysis were performed on ileum and lung samples. KYP-2047 treatment ameliorated histological alteration in ileum and lung, reduced collagen amount and lowered inflammatory protein levels. Moreover, TGF-β1, eNOS, VEGF and CD34 positive staining has been modulated; also, a reduction in apoptosis expression was confirmed. This research revealed the strong anti-inflammatory potential of KYP-2047 associated to its modulatory role on angiogenesis and apoptosis, suggesting POP as a novel therapeutic target for ALI after II/R.

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“…To evaluate the degree of fibrosis, tissue sections from saphene veins were stained with Masson trichrome according to the manufacturer’s protocol (Bio-Optica, Milan, Italy), as previously described [ 23 ]. Particularly, the entire area represented by the three tunicae, surrounding the veins, was considered for the quantification of the collagen in each section.…”

Section: Methodsmentioning

confidence: 99%

The Inhibition of Prolyl Oligopeptidase as New Target to Counteract Chronic Venous Insufficiency: Findings in a Mouse Model

et al. 2020

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(1) Background: Chronic venous insufficiency (CVI) is a common disorder related to functional and morphological abnormalities of the venous system. Inflammatory processes and angiogenesis alterations greatly concur to the onset of varicose vein. KYP-2047 is a selective inhibitor of prolyl oligopeptidase (POP), a serine protease involved in the release of pro-angiogenic molecules. The aim of the present study is to evaluate the capacity of KYP-2047 to influence the angiogenic and inflammatory mechanisms involved in the pathophysiology of CVI. (2) Methods: An in vivo model of CVI-induced by saphene vein ligation (SVL) and a tissue block culture study were performed. Mice were subjected to SVL followed by KYP-2047 treatment (intraperitoneal, 10 mg/kg) for 7 days. Histological analysis, Masson’s trichrome, Van Gieson staining, and mast cells evaluation were performed. Release of cytokines, nitric oxide synthase production, TGF-beta, VEGF, α-smooth muscle actin, PREP, Endoglin, and IL-8 quantification were investigated. (3) Results: KYP-2047 treatment ameliorated the histological abnormalities of the venous wall, reduced the collagen increase and modulated elastin content, lowered cytokines levels and prevented mast degranulation. Moreover, a decreased expression of TGF-beta, eNOS, VEGF, α-smooth muscle actin, IL-8, and PREP was observed in in vivo study; also a reduction in VEGF and Endoglin expression was confirmed in tissue block culture study. (4) Conclusions: For the first time, this research, highlighting the importance of POP as new target for vascular disorders, revealed the therapeutic potential of KYP-2047 as a helpful treatment for the management of CVI.

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Unique wreath-like smooth muscle proliferation of the pulmonary vasculature in pulmonary veno-occlusive disease versus pulmonary arterial hypertension

Cited by 5 publications

References 30 publications

The Unexpected Role of GCN2 Kinase Activation in Mediating Pulmonary Arterial Hypertension

The Unexpected Role of GCN2 Kinase Activation in Mediating Pulmonary Arterial Hypertension

The protective role of Prolyl oligopeptidase (POP) inhibition in acute lung injury induced by intestinal ischemia-reperfusion

The Inhibition of Prolyl Oligopeptidase as New Target to Counteract Chronic Venous Insufficiency: Findings in a Mouse Model

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