#SU5416

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Sulforaphane prevents right ventricular injury and reduces pulmonary vascular remodeling in pulmonary arterial hypertension.

PMID:  Am J Physiol Heart Circ Physiol. 2020 Apr 1 ;318(4):H853-H866. Epub 2020 Feb 28. PMID: 32108526 Abstract Title:  Sulforaphane prevents right ventricular injury and reduces pulmonary vascular remodeling in pulmonary arterial hypertension. Abstract:  Right ventricular (RV) dysfunction is the main determinant of mortality in patients with pulmonary arterial hypertension (PAH) and while inflammation is pathogenic in PAH, there is limited information on the role of RV inflammation in PAH. Sulforaphane (SFN), a potent Nrf2 activator, has significant anti-inflammatory effects and facilitates cardiac protection in preclinical diabetic models. Therefore, we hypothesized that SFN might play a comparable role in reducing RV and pulmonary inflammation and injury in a murine PAH model. We induced PAH using SU5416 and 10% hypoxia (SuHx) for 4 wk in male mice randomized to SFN at a daily dose of 0.5 mg/kg 5 days per week for 4 wk or to vehicle control. Transthoracic echocardiography was performed to characterize chamber-specific ventricular function during PAH induction. At 4 wk, we measured RV pressure and relevant measures of histology and protein and gene expression. SuHx induced progressive RV, but not LV, diastolic and systolic dysfunction, and RV and pulmonary remodeling, fibrosis, and inflammation. SFN prevented SuHx-induced RV dysfunction and remodeling, reduced RV inflammation and fibrosis, upregulated Nrf2 expression and its downstream gene NQO1, and reduced the inflammatory mediator leucine-rich repeat and pyrin domain-containing 3 (NLRP3). SFN also reduced SuHx-induced pulmonary vascular remodeling, inflammation, and fibrosis. SFN alone had no effect on the heart or lungs. Thus, SuHx-induced RV and pulmonary dysfunction, inflammation, and fibrosis can be attenuated or prevented by SFN, supporting the rationale for further studies to investigate SFN and the role of Nrf2 and NLRP3 pathways in preclinical and clinical PAH studies.Pulmonary arterial hypertension (PAH) in this murine model (SU5416 + hypoxia) is associated with early changes in right ventricular (RV) diastolic and systolic function. RV and lung injury in the SU5416 + hypoxia model are associated with markers for fibrosis, inflammation, and oxidative stress. Sulforaphane (SFN) alone for 4 wk has no effect on the murine heart or lungs. Sulforaphane (SFN) attenuates or prevents the RV and lung injury in the SUF5416 + hypoxia model of PAH, suggesting that Nrf2 may be a candidate target for strategies to prevent or reverse PAH.

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Microwave radiation may damage the blood brain barrier, according to this in vitro study.

PMID:  Mol Neurobiol. 2015 Aug ;52(1):478-91. Epub 2014 Sep 9. PMID: 25195697 Abstract Title:  Activation of VEGF/Flk-1-ERK Pathway Induced Blood-Brain Barrier Injury After Microwave Exposure. Abstract:  Microwaves have been suggested to induce neuronal injury and increase permeability of the blood-brain barrier (BBB), but the mechanism remains unknown. The role of the vascular endothelial growth factor (VEGF)/Flk-1-Raf/MAPK kinase (MEK)/extracellular-regulated protein kinase (ERK) pathway in structural and functional injury of the blood-brain barrier (BBB) following microwave exposure was examined. An in vitro BBB model composed of the ECV304 cell line and primary rat cerebral astrocytes was exposed to microwave radiation (50 mW/cm(2), 5 min). The structure was observed by scanning electron microscopy (SEM) and the permeability was assessed by measuring transendothelial electrical resistance (TEER) and horseradish peroxidase (HRP) transmission. Activity and expression of VEGF/Flk-1-ERK pathway components and occludin also were examined. Our results showed that microwave radiation caused intercellular tight junctions to broaden and fracture with decreased TEER values and increased HRP permeability. After microwave exposure, activation of the VEGF/Flk-1-ERK pathway and Tyr phosphorylation of occludin were observed, along with down-regulated expression and interaction of occludin with zonula occludens-1 (ZO-1). After Flk-1 (SU5416) and MEK1/2 (U0126) inhibitors were used, the structure and function of the BBB were recovered. The increase in expression of ERK signal transduction molecules was muted, while the expression and the activity of occludin were accelerated, as well as the interactions of occludin with p-ERK and ZO-1 following microwave radiation. Thus, microwave radiation may induce BBB damage by activating the VEGF/Flk-1-ERK pathway, enhancing Tyr phosphorylation of occludin, while partially inhibiting expression and interaction of occludin with ZO-1.

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