Hsp90 inhibitors induce the unfolded protein response in bovine and mice lung cells

Growth hormone releasing hormone is a hypothalamic neuropeptide, which regulates the release of growth hormone from the anterior pituitary gland. Growth hormone releasing hormone antagonists are anticancer agents, associated with strong anti-inflammatory activities. In the present study, we investigated the effects of the GHRH antagonist MIA-602 in the integrity of the brain microvascular endothelium in vitro. Our observations suggest that MIA-602 protects against the H2O2-induced breakdown of the brain endothelium and enhances its integrity by inducing P53, deactivating cofilin, and suppressing the RhoA inflammatory pathway. Thus, GHRH antagonists may offer an exciting possibility for the treatment of pathologies related to the blood brain barrier dysfunction, including the Parkinson’s and Alzheimer’s diseases.

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“…The β-actin antibody (1:5000) was used as a loading control in the case of P53. The reagents were purchased from VWR (Radnor, PA, USA) [15].…”

Section: Western Blot Analysismentioning

confidence: 99%

GHRH Antagonists Protect Against Hydrogen Peroxide-Induced Breakdown of Brain Microvascular Endothelium Integrity

et al. 2020

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“…To do so, it employs three sensors, namely the protein kinase RNA-like ER kinase, the activating transcription factor 6 and the inositol-requiring enzyme-1α. It was recently shown that Hsp90 inhibitors induce UPR activation and that GHRH antagonists elevate the endoplasmic reticulum stress (10). Hence, an efficient therapeutic approach toward ARDS may arise by the development of novel agents that are able to stochastically induce those UPR branches that are involved in the repair of the lung endothelium.…”

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confidence: 99%

P53 in lung vascular barrier dysfunction

Barabutis

2020

Vascular Biology

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Endothelial barrier dysfunction is the hallmark of inflammatory lung disease, including Acute Lung Injury and Acute Respiratory Distress Syndrome. The purpose of the present editorial is to emphasize on recent advances in the corresponding field, as it relates to P53. This tumor suppressor protein has been shown to enhance the vascular barrier integrity via distinct molecular pathways. Further, it mediates the beneficial effects of heat shock protein 90 inhibitors and growth hormone releasing hormone antagonists in the lung microvasculature.

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“…Those anti-cancer and anti-inflammatory agents induce UPR both in vivo and in vitro. Hence, the existence of a new molecular network in the context of P53/UPR/Hsp90 [29], which operates towards the repair of the severely inflamed lungs, is highly possible [30,31]. Pharmacological "fine-tuning" of that meticulously orchestrated network, may deliver novel ways to restore respiratory functions in the hospitalized ARDS patients.…”

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confidence: 99%