Abstract
Recent studies have suggested a pathogenetic link between ischemic stroke and Takotsubo cardiomyopathy (TCM) with poor outcome, when occurring simultaneously. Increased catecholamine (CAT) levels as well as elevated inflammatory mediators (INF) are found in the blood of patients with ischemic stroke concomitant with Takotsubo syndrome (TTS). On molecular level, the impact of these stressors combined with hypoxemia could compromise the integrity of the blood brain barrier (BBB) resulting in poor outcomes. As a first step in the direction of investigating possible molecular mechanisms, an in vitro model of the described pathological constellation was designed. An immortalized murine microvascular endothelial cell line from the cerebral cortex (cEND) was used as an established in vitro model of the BBB. cEND cells were treated with supraphysiological concentrations of CAT (dopamine, norepinephrine, epinephrine) and INF (TNF-α and Interleukin-6). Simultaneously, cells were exposed to oxygen glucose deprivation (OGD) as an established in vitro model of ischemic stroke with/without subsequent reoxygenation. We investigated the impact on cell morphology and cell number by immunofluorescence staining. Furthermore, alterations of selected tight and adherens junction proteins forming paracellular barrier as well as integrins mediating cell-matrix adhesion were determined by RT-PCR and/or Western Blot technique. Especially by choosing this wide range of targets, we give a detailed overview of molecular changes leading to compromised barrier properties. Our data show that the proteins forming the BBB and the cell count are clearly influenced by CAT and INF applied under OGD conditions. Most of the investigated proteins are downregulated, so a negative impact on barrier integrity can be assumed. The structures affected by treatment with CAT and INF are potential targets for future therapies in ischemic stroke and TTS.
Highlights
Recent clinical publications and literature reviews point out that takotsubo syndrome (TTS) occurring in combination with ischemic stroke is a notable clinical constellation [1]
We suggest that the severity of ischemic stroke in patients with Takotsubo syndrome (TTS) is caused by aggravated dysfunction of the blood brain barrier (BBB)
The present study provides a comprehensive overview of molecular changes of cerebral microvascular endothelium, exposed to an in vitro simulation of characteristic laboratory findings in patients suffering from TTS and ischemic stroke simultaneously
Summary
Recent clinical publications and literature reviews point out that takotsubo syndrome (TTS) occurring in combination with ischemic stroke is a notable clinical constellation [1]. The link between these two pathologies is not well-understood yet, especially not on molecular level. Takotsubo cardiomyopathy (TCM) is a cardiac pathology at first glance mimicking acute coronary syndrome (ACS). The most important clinical feature is the absence of coronary occlusion which differentiates TCM from ACS [2]. Characteristic wall motion abnormalities predominantly affecting the left ventricle are observed. This phenomenon is described as apical ballooning. In one to two thirds of patients suffering from TCM, a previous psychically or physically stressful trigger can be identified [3, 4]
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