Activation of Sigma-1 Receptor Enhanced Pericyte Survival via the Interplay Between Apoptosis and Autophagy: Implication
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ORIGINAL ARTICLE
Activation of Sigma-1 Receptor Enhanced Pericyte Survival via the Interplay Between Apoptosis and Autophagy: Implications for Blood–Brain Barrier Integrity in Stroke Yuan Zhang 1 & Xiaotian Zhang 2 & Qiangqiang Wei 3 & Shuo Leng 4 & Cai Li 5 & Bing Han 1 & Ying Bai 1 & Huibin Zhang 6 & Honghong Yao 1,7 Received: 18 January 2019 / Revised: 21 May 2019 / Accepted: 6 June 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract Stroke is a cerebrovascular disorder that affects many people worldwide. Pericytes play an important role in stroke progression and recovery. The sigma-1 receptor (σ-1R) signaling pathway has been suggested as having promising neuroprotective potential in treating stroke; however, whether σ-1R activation regulates pericyte function remains unknown. The aim of this study was to elucidate the role of σ-1R and a novel σ-1R agonist in pericytes following ischemic stroke. An ischemic stroke animal model was induced by photothrombotic middle cerebral artery occlusion (pMCAO) in σ-1R knockout (KO) and wild-type (WT) mice. After pMCAO, there was significant pericyte loss and coverage in σ-1R KO mice compared with WT mice as determined using transmission electron microscopy, immunofluorescence staining, and western blot. Interestingly, a novel σ-1R agonist decreased infarct volume and blood–brain barrier damage with a concomitant amelioration of pericyte loss, as determined by western blot. Further studies indicated that cell apoptosis and autophagy were induced in an in vivo pMCAO ischemic stroke animal model and an in vitro oxygen glucose deprivation-treatment group. Inhibition of autophagy using a pharmacological approach significantly mitigated pericyte apoptosis, suggesting that autophagy was upstream of apoptosis in pericytes. Both in vivo and in vitro studies indicated that the σ-1R agonist significantly decreased cell apoptosis via inhibition of autophagy with a subsequent enhancement of pericyte survival. This study identified the unique roles for σ-1R in mediating pericyte survival via the regulation of the interplay between apoptosis and autophagy, suggesting that a novel σ-1R agonist may be a promising therapeutic agent for the treatment of stroke patients. Keywords Stroke . Sigma-1 receptor . Blood–brain barrier . Pericyte . Apoptosis . Autophagy
Yuan Zhang, Xiaotian Zhang, Qiangqiang Wei and Shuo Leng contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12975-019-00711-0) contains supplementary material, which is available to authorized users. * Yuan Zhang [email protected] * Huibin Zhang [email protected]
4
Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, Jiangsu, China
5
Department of Neurology, Rizhao Hospital of Traditional Chinese Medicine, Rizhao 276800, Shandong, China
6
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pha
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