Pathophysiological roles of nuclear factor kappaB (NF-kB) in pulmonary arterial hypertension: effects of synthetic selective NF-kB inhibitor IMD-0354

Hosokawa, Susumu; Haraguchi, Go; Sasaki, Akiko; Arai, Hirokuni; Muto, Shoshi; Itai, Akiko; S, Doi; Mizutani, Shuki; Isobe, Mitsuaki

doi:10.1093/cvr/cvt105

Cited by 85 publications

(63 citation statements)

References 35 publications

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“…The protective mechanism seems to be associated with restoration of BMPR2-Id-Notch-3 axis molecules, attenuation of inflammatory response, reduction of cell death in lung ECs, and reversal of EndMT process. Inhibition of NF-κB by pharmacological intervention or genetic manipulation or by nanoparticle (decoy of NF-κB) delivery has been reported to show protection, 5,[7][8][9]15,23,24 but this report provides for the first time that genetic inhibition of NF-κB in the lungs prevents the progression of PAH and RVH. Our study provides the following evidences in regards to the mechanism of MCT-induced PAH and RVH.…”

Section: Discussionmentioning

confidence: 80%

Inhibition of Nuclear Factor-κB in the Lungs Prevents Monocrotaline-Induced Pulmonary Hypertension in Mice

Wei

Kim

et al. 2014

Hypertension

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P ulmonary arterial hypertension (PAH) is characterized by multicellular vascular lesions which obstruct and obliterate pulmonary arteries. The occluded vessels impede blood flow and increase right ventricular (RV) afterload leading to RV hypertrophy (RVH) and RV failure.1,2 The pathogenesis of PAH is multifactorial and involves vascular cell remodeling including pulmonary arterial endothelial cell (EC) dysfunction and pulmonary arterial smooth muscle cell proliferation. 3,4 Treatment regimens for PAH include inhaled nitric oxide, vasodilators, calcium channel blockers, intravenous prostacyclin, and endothelin receptor antagonists, which fail to fully reverse this disease.5 Identifying key pathways is, therefore, required for the development of new targeted therapeutics.Nuclear factor-κB (NF-κB) is a key transcriptional regulator in various cardiac disorders (myocardial infarction, hypertrophy, and dilated cardiomyopathy, etc), 6,7 but the role of NF-κB remains limited in PAH-induced vascular remodeling and RVH. Recent few reports advocate the critical role of NF-κB in the progression or setting of PAH, [8][9][10] but the underlying mechanism of monocrotaline (MCT)-induced PAH and its progression to the development of RVH remains elusive. MCT is a plant alkaloid contained in the seeds of Crotalaria spectalalia and its metabolite, MCT pyrrole, injures the ECs of pulmonary blood vessels.11 It is suggested that MCT treatment causes direct damage of ECs, increases alveolar capillary permeability, and induces inflammation that triggers the development of PAH and further progresses to RVH.12-14 Despite its frequent use for many decades, the basic mechanism underlying PAH induction by MCT has not been fully understood.We demonstrated previously that MCT-treated PAH-induced RVH was attenuated in cardiac-specific IκBα triple mutant transgenic mice, compared with wild-type (WT) mice, suggesting a protective role of NF-κB in RVH. 15 We identified bone morphogenetic protein (BMP), BMP receptor (BMPR), inhibitor of differentiation (Id), SMAD, and the Notch (BMP-SMAD-Id-Notch) axis as an integral signaling Abstract-Pulmonary arterial hypertension (PAH) is a devastating cardiopulmonary disorder with significant morbidity and mortality in patients with various lung and heart diseases. PAH is characterized by vascular obstruction which leads to a sustained increased pulmonary vascular resistance, vascular remodeling, and right ventricular hypertrophy and failure. Limited PAH therapies indicate that novel approaches are urgently needed for the treatment of PAH. Nuclear factor-κB (NF-κB) has been shown to play an important role in different cardiac pathologies; however, the role of NF-κB remains limited in the setting of PAH. Here, we investigated whether NF-κB inhibition in the lungs using Club (Clara) cell-10 promoter driving IκBα mutant had any effect in monocrotaline (MCT)-induced PAH mouse model. Our data revealed that MCT-induced PAH and right ventricular hypertrophy were associated with NF-κB activation, inflammatory respon...

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Section: Discussionmentioning

confidence: 80%

Inhibition of Nuclear Factor-κB in the Lungs Prevents Monocrotaline-Induced Pulmonary Hypertension in Mice

Wei

Kim

et al. 2014

Hypertension

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“…Previously the same concentration of IMD‐0354 was successfully used in rats in vivo to block NF‐ κ B pathway (Hosokawa et al. 2013). Surprisingly, preservation of the I κ B α content in unloaded muscle in our experiments has not prevented muscle atrophy.…”

Section: Discussionmentioning

confidence: 99%

“…The IMD‐0354 dose used in our experiments is comparable to previously published data (Hosokawa et al. 2013). The control animals received equal volumes of 1% DMSO/saline vehicle solution using Hamilton syringe with a very fine needle.…”

Section: Methodsmentioning

confidence: 99%

Paradoxical effect of IKKβ inhibition on the expression of E3 ubiquitin ligases and unloading-induced skeletal muscle atrophy

et al. 2017

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We tested whether NF‐κB pathway is indispensable for the increase in expression of E3‐ligases and unloading‐induced muscle atrophy using IKKβ inhibitor IMD‐0354. Three groups of rats were used: nontreated control (C), 3 days of unloading/hindlimb suspension with (HS+IMD) or without (HS) IMD‐0354. Levels of IκBα were higher in HS+IMD (1.16‐fold) and lower in HS (0.82‐fold) when compared with C group. IMD‐0354 treatment during unloading: had no effect on loss of muscle mass; increased mRNA levels of MuRF1 and MAFbx; increased level of pFoxO3; and had no effect on levels of Bcl‐3, p105, and p50 proteins. Our study for the first time showed that inhibiting IKK β in vivo during 3‐day unloading failed to diminish expression of ubiquitin ligases and prevent muscle atrophy.

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“…8 Additionally, recent studies are discovering a nuclear factor-κB (NF-κB) inflammatory signaling pathway in PAH. 9 All of these elements combine to cause increased pulmonary vascular resistance, pulmonary hypertension, and ultimately, progressive right heart failure. 8 Broadly related to the pathogenesis of PAH, the systemic inflammatory process underlying psoriasis has been known to cause endothelial dysfunction, 6,10 and platelet activation in psoriasis has been show to promote a prothrombotic state.…”

Section: Discussionmentioning

confidence: 99%

Incidence of Pulmonary Arterial Hypertension in Patients with Psoriasis: A Retrospective Cohort Study

Choi

Famenini

2017

TPJ

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Context: Inflammatory signaling may play an important role in the pathogenesis of pulmonary arterial hypertension (PAH).Objective: To assess the incidence of PAH in patients with mild and severe psoriasis compared with their respective controls. Results: There were 10,115 patients with mild psoriasis, 3821 with severe psoriasis, and 69,360 matched controls. On multivariable analysis, there was a significantly increased risk of PAH developing in the severe psoriasis cohort vs their controls (hazard ratio = 1.46, 95% confidence interval = 1.09-1.94). Conclusion:The systemic inflammatory process underlying psoriasis may be a cause for an increased risk of PAH, but there are numerous secondary causes of PAH, some of which were not accounted for in our study. Further prospective, randomized controlled trials are necessary to establish psoriasis as a risk factor for PAH.

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Pathophysiological roles of nuclear factor kappaB (NF-kB) in pulmonary arterial hypertension: effects of synthetic selective NF-kB inhibitor IMD-0354

Abstract: We speculate that the positive-feedback loop (Erk1/2-NF-kB-MCP-1-Erk1/2) is associated with progression of PAH by causing FGF₂-induced inflammation in MCT rats. IMD-0354 has potential as a new therapeutic tool for PAH.

Cited by 85 publications

References 35 publications

Inhibition of Nuclear Factor-κB in the Lungs Prevents Monocrotaline-Induced Pulmonary Hypertension in Mice

Inhibition of Nuclear Factor-κB in the Lungs Prevents Monocrotaline-Induced Pulmonary Hypertension in Mice

Paradoxical effect of IKKβ inhibition on the expression of E3 ubiquitin ligases and unloading-induced skeletal muscle atrophy

Incidence of Pulmonary Arterial Hypertension in Patients with Psoriasis: A Retrospective Cohort Study

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