RAGE-mediated extracellular matrix proteins accumulation exacerbates HySu-induced pulmonary hypertension

Jia, Daile; He, Yuefeng; Zhu, Qian; Liu, Huan; Zuo, Caojian; Chen, Guilin; Yu, Ying; Lü, Ankang

doi:10.1093/cvr/cvx051

Cited by 42 publications

(46 citation statements)

References 31 publications

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“…vascular endothelial growth factor [VEGF]). Limited available evidence suggests that HMGB-1 production is upregulated during hypoxia and that RAGE activation contributes the development of hypoxia-induced pulmonary hypertension (Jia et al 2017). Membrane bound RAGE is very difficult to measure in vivo, however soluble forms of RAGE (sRAGE) also exist and possess a similar affinity for ligands to mRAGE.…”

Section: Vol 67mentioning

confidence: 99%

The Effects of Acute Hypoxia on Tissue Oxygenation and Circulating Alarmins in Healthy Adults

Boos

Lamb²,

Midwinter³

et al. 2018

Physiol Res

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The binding of high-mobility group box-1 (HMGB-1) to the membrane receptor for advanced glycation end-products (mRAGE) is a key early mediator of non-infectious inflammation and its triggers include ischaemia/hypoxia. The effects of acute hypoxia on soluble RAGE (sRAGE) are unknown. Fourteen healthy adults (50 % women; 26.6±3.8 years) were assessed at baseline normoxia (T0), followed by four time-points (T90, 95, 100 and 180 min) over three hours of continuous normobaric hypoxia (NH, 4,450 m equivalent) and again 60 min after return to normoxia (T240). A 5-min exercise step test was performed during NH at T90. Plasma concentrations of HMGB-1, sRAGE VCAM-1, ICAM-1, VEGF IL-8 and IL-13 were measured using venous blood. Arterial and tissue oxygen saturations were measured using pulse oximetry (SpO2) and near-infrared spectroscopy (StO2), respectively. NH led to a significant reduction in SpO2, StO2, sRAGE and VEGF, which was compounded by exercise, before increasing to baseline values with normoxic restoration (T240). NH-exercise led to a paired increase in HMGB-1. sRAGE inversely correlated with HMGB-1 (r=-0.32; p=0.006), heart rate (r=-0.43; p=0.004) but was not linked to SpO2 or StO2. In conclusion, short-term NH leads to a fall in sRAGE and VEGF concentrations with a transient rise post NH-exercise in HMGB-1.

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Section: Vol 67mentioning

confidence: 99%

The Effects of Acute Hypoxia on Tissue Oxygenation and Circulating Alarmins in Healthy Adults

Boos

Lamb²,

Midwinter³

et al. 2018

Physiol Res

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“…35 Levels of RAGE have been reported to be elevated in patients with PH. [44][45][46] Interaction of elevated levels of AGE and RAGE would increase the production of ROS, proinflammatory cytokines, and vascular remodeling. Serum levels of sRAGE are variable in patients with PH and associated diseases.…”

Section: Discussionmentioning

confidence: 99%

“…43 There is an increased expression of RAGE in smooth muscle cells of the pulmonary artery under hypoxic conditions in both humans and mice. 44 These authors also showed that the expression of RAGE was upregulated in pulmonary artery in hypoxia plus Sugen5416 (SU5416)-induced PAH mice. They also demonstrated that RAGE deletion reduced the PA pressure and restrained ECM accumulation in PA of the mouse model.…”

Section: Serum Levels Of Age In Phmentioning

confidence: 96%

“…Blocking RAGE activity with neutralizing antibody or genetic deletion of RAGE reduced ECM protein accumulation. 44 RAGE is one of the most upregulated proteins in PAH lung tissue of PAH patients. 45 There is an increase in the RAGE mRNA levels in human pulmonary hypertensive lung tissue compared with normotensive lung tissue, and an increase in RAGE protein levels in pulmonary artery in human pulmonary hypertensive patients compared with normotensive pulmonary artery (five-fold increase).…”

Section: Serum Levels Of Age In Phmentioning

confidence: 99%

“…62 RAGE mediates deposition of ECM fibronectin and collagen through activation of transforming growth factor-β1. 44 Vascular remodeling of the PA in PAH is characterized by deposition of ECM. 63 Binding of RAGE with HMGB-1 induces proliferation and migration of fibroblasts which are prevented by RAGE antibody.…”

Section: Mechanism Of Age-rage-induced Pulmonary Hypertensionmentioning

confidence: 99%

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AGE–RAGE Stress in the Pathophysiology of Pulmonary Hypertension and its Treatment

Prasad

2019

Int J Angiol

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Pulmonary hypertension (PH) is a rare and fatal disease characterized by elevation of pulmonary artery pressure ≥ 25 mm Hg. There are five groups of PH: (1) pulmonary artery (PA) hypertension (PAH), (2) PH due to heart diseases, (3) PH associated with lung diseases/hypoxia, (4) PH associated with chronic obstruction of PA, and (5) PH due to unclear and/or multifactorial mechanisms. The pathophysiologic mechanisms of group 1 have been studied in detail; however, those for groups 2 to 5 are not that well known. PH pathology is characterized by smooth muscle cells (SMC) proliferation, muscularization of peripheral PA, accumulation of extracellular matrix (ECM), plexiform lesions, thromboembolism, and recanalization of thrombi. Advanced glycation end products (AGE) and its receptor (RAGE) and soluble RAGE (sRAGE) appear to be involved in the pathogenesis of PH. AGE and its interaction with RAGE induce vascular hypertrophy through proliferation of vascular SMC, accumulation of ECM, and suppression of apoptosis. Reactive oxygen species (ROS) generated by interaction of AGE and RAGE modulates SMC proliferation, attenuate apoptosis, and constricts PA. Increased stiffness in the artery due to vascular hypertrophy, and vasoconstriction due to ROS resulted in PH. The data also suggest that reduction in consumption and formation of AGE, suppression of RAGE expression, blockage of RAGE ligand binding, elevation of sRAGE levels, and antioxidants may be novel therapeutic targets for prevention, regression, and slowing of progression of PH. In conclusion, AGE–RAGE stress may be involved in the pathogenesis of PH and the therapeutic targets should be the AGE–RAGE axis.

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Intravenous Delivery of Lung‐Targeted Nanofibers for Pulmonary Hypertension in Mice

Marulanda

Mercel

Gillis

et al. 2021

Adv Healthcare Materials

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Pulmonary hypertension is a highly morbid disease with no cure. Available treatments are limited by systemic adverse effects due to non‐specific biodistribution. Self‐assembled peptide amphiphile (PA) nanofibers are biocompatible nanomaterials that can be modified to recognize specific biological markers to provide targeted drug delivery and reduce off‐target toxicity. Here, PA nanofibers that target the angiotensin I‐converting enzyme and the receptor for advanced glycation end‐products (RAGE) are developed, as both proteins are overexpressed in the lung with pulmonary hypertension. It is demonstrated that intravenous delivery of RAGE‐targeted nanofibers containing the targeting epitope LVFFAED (LVFF) significantly accumulated within the lung in a chronic hypoxia‐induced pulmonary hypertension mouse model. Using 3D light sheet fluorescence microscopy, it is shown that LVFF nanofiber localization is specific to the diseased pulmonary tissue with immunofluorescence analysis demonstrating colocalization of the targeted nanofiber to RAGE in the hypoxic lung. Furthermore, biodistribution studies show that significantly more LVFF nanofibers localized to the lung compared to major off‐target organs. Targeted nanofibers are retained within the pulmonary tissue for 24 h after injection. Collectively, these data demonstrate the potential of a RAGE‐targeted nanomaterial as a drug delivery platform to treat pulmonary hypertension.

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RAGE-mediated extracellular matrix proteins accumulation exacerbates HySu-induced pulmonary hypertension

Cited by 42 publications

References 31 publications

The Effects of Acute Hypoxia on Tissue Oxygenation and Circulating Alarmins in Healthy Adults

The Effects of Acute Hypoxia on Tissue Oxygenation and Circulating Alarmins in Healthy Adults

AGE–RAGE Stress in the Pathophysiology of Pulmonary Hypertension and its Treatment

Intravenous Delivery of Lung‐Targeted Nanofibers for Pulmonary Hypertension in Mice

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