Inflammatory cytokines in pulmonary hypertension

Excessive proliferation of human pulmonary artery smooth muscle cells (HPASMC) is one of the major factors that trigger vascular remodeling in hypoxia-induced pulmonary hypertension. Several studies have implicated that hypoxia inhibits the tumor suppressor p21 (CDKN1A). However, the precise mechanism is unknown. The mouse model of hypoxia-induced PH and in vitro experiments were used to assess the impact of microRNAs (miRNAs) on the expression of CDKN1A. In these experiments, the miRNA family miR-130 was identified to regulate the expression of CDKN1A. Transfection of HPASMC with miR-130 decreased the expression of CDKN1A and, in turn, significantly increased smooth muscle proliferation. Conversely, inhibition of miR-130 by anti-miRs and seed blockers increased the expression of CDKN1A. Reporter gene analysis proved a direct miR-130-CDKN1A target interaction. Exposure of HPASMC to hypoxia was found to induce the expression of miR-130 with concomitant decrease of CDKN1A. These findings were confirmed in the mouse model of hypoxia-induced pulmonary hypertension showing that the use of seed blockers against miR-130 restored the expression of CDKN1A. These data suggest that miRNA family miR-130 plays an important role in the repression of CDKN1A by hypoxia. miR-130 enhances hypoxia-induced smooth muscle proliferation and might be involved in the development of right ventricular hypertrophy and vascular remodeling in pulmonary hypertension. AbstractExcessive proliferation of human pulmonary artery smooth muscle cells (HPASMC) is one of the major factors that trigger vascular remodeling in hypoxia-induced pulmonary hypertension. Several studies have implicated that hypoxia inhibits the tumour suppressor p21 (CDKN1A). However, the precise mechanism is unknown. The mouse model of hypoxia-induced PH and in vitro experiments were used to assess the impact of microRNAs (miRNAs) on the expression of CDKN1A. In these experiments, the miRNA family miR-130 was identified to regulate the expression of CDKN1A. Transfection of HPASMC with miR-130 decreased the expression of CDKN1A and, in turn, significantly increased smooth muscle proliferation. Conversely, inhibition of miR-130 by anti-miRs and seed blockers increased the expression of CDKN1A. Reporter gene analysis proved a direct miR-130 -CDKN1A target interaction. Exposure of HPASMC to hypoxia was found to induce the expression of miR-130 with concomitant decrease of CDKN1A. These findings were confirmed in the mouse model of hypoxia-induced pulmonary hypertension showing that the use of seed blockers against miR-130 restored the expression of CDKN1A.These data suggest that miRNA family miR-130 plays an important role in the repression of CDKN1A by hypoxia. miR-130 enhances hypoxia-induced smooth muscle proliferation and might be involved in the development of right ventricular hypertrophy and vascular remodeling in pulmonary hypertension.

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“…miRNAs of the cluster miR-17/92 have been implicated to silence BMPR2 11 , 22 . Since miRNAs act in a pleiotropic manner, i.e.…”

Section: Discussionmentioning

confidence: 99%

The hypoxia-induced microRNA-130a controls pulmonary smooth muscle cell proliferation by directly targeting CDKN1A

Brock

Haider

Vogel

et al. 2015

The International Journal of Biochemistry & Cell Biology

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“…13,14 Evidence from studies in animal models and in patients with pulmonary hypertension suggests that inflammation contributes to the development of PAH. [12][13][14][15][16] In lung biopsies from patients with PAH, infiltration of inflammatory cells, including macrophages and T and B lymphocytes, and dendritic cells is found in pulmonary perivascular spaces and around the plexiform lesions in PAH. 17,18 Activation of macrophages induces the release of cytokines, such as tumor necrosis factor-α, IL-1β, and IL-6, which all are major contributing factors in the pathogenesis of PAH.…”

Section: Discussionmentioning

confidence: 99%

“…1,2,22 Inflammatory processes play an important role in the cardiopulmonary remodeling of PAH. [13][14][15][16] The degree of perivascular inflammation correlates with both vascular wall thickness and the mean pulmonary arterial pressure. 18 Cytokines/chemokines and hypoxia are key players in the pathogenesis of PAH by mediating the excess cellular proliferation and pulmonary vascular remodeling.…”

Section: Discussionmentioning

confidence: 99%

“…18 Cytokines/chemokines and hypoxia are key players in the pathogenesis of PAH by mediating the excess cellular proliferation and pulmonary vascular remodeling. [13][14][15][16] Human atherosclerotic lesions express high level of B1 receptors. 21 Kinin B1 receptors mediate vascular remodeling and leukocyte invasion (monocytes) into the perivascular tissue in mice and rats.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of Kinin B1 Receptors Attenuates Pulmonary Hypertension and Vascular Remodeling

et al. 2015

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P ulmonary arterial hypertension (PAH) is a progressive disease characterized by persistent increases in pulmonary arterial pressure. This increasing pressure is associated with perivascular inflammation, excessive pulmonary vascular proliferation, remodeling, and vasoconstriction. Ultimately, PAH can cause right heart failure and death.1-3 Despite new treatment options, PAH patients still face high mortality rates. [1][2][3] Therefore, it is necessary to develop additional novel therapeutic approaches that target the various components of this multifactorial disease. [1][2][3] Kinins are proinflammatory peptides that exert a variety of biological actions via stimulation of 2 pharmacologically distinct receptor subtypes, B1 and B2. 4,5 The former are normally weakly expressed, but can be upregulated in the presence of cytokines and endotoxins or during tissue injury, whereas the latter are expressed constitutively. 4,5 One important difference between the 2 subtypes is that the B2 is internalized rapidly and desensitizes, whereas kinin B1 receptor-induced responses are more persistent and suggesting the lack of the internalization of the B1 receptorligand complex.4-6 Thus, kinin B1 receptors represent a novel therapeutic target for chronic inflammatory diseases. 4-6Kinin B1 receptors are involved in diverse pathological processes, including inflammation, smooth muscle contraction, increased vascular permeability, edema, pain, cytokine and chemokine release, cell proliferation, and vascular and myocardial remodeling. [4][5][6][7][8][9] In contrast to the B2 receptormediated relaxation to bradykinin, B1 receptors mediate vasoconstriction in cardiopulmonary vascular beds. 8,10,11 We hypothesized that kinin B1 receptors may play an important role in the pathogenesis of PAH. With this same reasoning, B1 receptor antagonists may have therapeutic potential for treating PAH by reducing inflammation, inhibiting smooth muscle contraction, attenuating vascular and cardiac remodeling, and improving cardiac function.The small molecule BI113823 is a newly developed, orally active, nonpeptide B1 receptor antagonist that exerts a potent anti-inflammatory effect with a favorable cardiovascular profile. 7,9 This study examined the effects of kinin B1 receptor blockade with BI113823 in a well-established experimental model of monocrotaline-induced PAH and vascular remodeling in left pneumonectomized rats. 12Abstract-This study examined whether the kinin B1 receptor is involved in the pathogenesis of pulmonary hypertension, and whether its inhibition could reduce inflammation, pulmonary hypertension, vascular remodeling, and right heart dysfunction. Male Wistar rats underwent left pneumonectomy. Seven days later, the rats were injected subcutaneously with monocrotaline (60 mg/kg). The rats were then randomly assigned to receive treatment with vehicle or with BI113823 (a selective B1 receptor antagonist, 30 mg/kg, twice per day) via oral gavage from the day of monocrotaline injection to day 28. By day 28, BI113823-treated rats had s...

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“…3,4 It is known that inflammation plays a pivotal role in disease progression in various types of PAH. [5][6][7][8] Inflammatory factors participate in vasoconstriction, promote hyperplasia of pulmonary vascular endothelial cells and smooth-muscle cells, and subsequently result in remodeling of the pulmonary vasculature. 9 In addition to an increase in inflammatory mediators, endothelial cell injury caused by increased blood flow also leads to mitochondrial dysfunction, which is the major source of reactive oxygen species (ROS) production in PAH.…”

Section: Introductionmentioning

confidence: 99%

Intratracheal instillation of ethyl pyruvate nanoparticles prevents the development of shunt-flow-induced pulmonary arterial hypertension in a rat model

Li¹,

Zhang²,

Cao³

et al. 2016

IJN

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Purpose:To investigate whether inhalation of ethyl pyruvate (EP) encapsulated with poly(ethylene glycol)-block-lactide/glycolide copolymer nanoparticles (EP-NPs) can prevent the development of shunt-flow-induced hyperkinetic pulmonary arterial hypertension (PAH) in a rat model. Materials and methods: Rats were separated into five groups: blank (ie, no treatment after shunt flow), normal control (ie, no shunt flow or treatment), EP-NP instillation, EP-only instillation, and vehicle. The animals received intratracheal instillation of EP-NPs or other treatments immediately after a shunt flow, and treatment continued weekly until the end of the experiment. Hemodynamic data were recorded, pulmonary arterial remodeling was assessed, and levels of inflammatory mediators and ET1 expression in the lung and serum were analyzed. In addition, retention of EP in the lungs of rats in the EP-NP and EP-only groups was measured using highperformance liquid chromatography. Results: After 12 weeks, hemodynamic abnormalities and pulmonary arterial remodeling were improved in the EP-NP instillation group, compared with the blank, EP-only, and vehicle groups (P,0.05). In addition, the EP-NP group showed significantly decreased levels of HMGB1, IL-6, TNFα, reactive oxygen species, and ET1 in the lung during PAH development (P,0.05). Furthermore, EP-NP instillation was associated with reduced serum levels of inflammatory factors and ET1. High-performance liquid-chromatography measurement indicated that EP retention was greater in the lungs of the EP-NP group than in the EP-only group. Conclusion: EP-NP instillation attenuated inflammation and prevented pulmonary arterial remodeling during the development of PAH induced by shunt flow. In the future, EP-NP delivery into the lung might provide a novel approach for preventing PAH.

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Inflammatory cytokines in pulmonary hypertension

Cited by 157 publications

References 67 publications

The hypoxia-induced microRNA-130a controls pulmonary smooth muscle cell proliferation by directly targeting CDKN1A

The hypoxia-induced microRNA-130a controls pulmonary smooth muscle cell proliferation by directly targeting CDKN1A

Inhibition of Kinin B1 Receptors Attenuates Pulmonary Hypertension and Vascular Remodeling

Intratracheal instillation of ethyl pyruvate nanoparticles prevents the development of shunt-flow-induced pulmonary arterial hypertension in a rat model

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