A review of the role of cav-1 in neuropathology and neural recovery after ischemic stroke

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Abstract

Ischemic stroke starts a series of pathophysiological processes that cause brain injury. Caveolin-1 (cav-1) is an integrated protein and locates at the caveolar membrane. It has been demonstrated that cav-1 can protect blood–brain barrier (BBB) integrity by inhibiting matrix metalloproteases (MMPs) which degrade tight junction proteins. This article reviews recent developments in understanding the mechanisms underlying BBB dysfunction, neuroinflammation, and oxidative stress after ischemic stroke, and focuses on how cav-1 modulates a series of activities after ischemic stroke. In general, cav-1 reduces BBB permeability mainly by downregulating MMP9, reduces neuroinflammation through influencing cytokines and inflammatory cells, promotes nerve regeneration and angiogenesis via cav-1/VEGF pathway, reduces apoptosis, and reduces the damage mediated by oxidative stress. In addition, we also summarize some experimental results that are contrary to the above and explore possible reasons for these differences.

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Temporal and spatial dynamics of cerebral immune cell accumulation in stroke.

Mathias Gelderblom, Frank Leypoldt, Karin Steinbach … (2009)

Ischemic stroke leads to significant morbidity and mortality in the Western world. Early reperfusion strategies remain the treatment of choice but can initiate and augment an inflammatory response causing secondary brain damage. The understanding of postischemic inflammation is very limited. The objectives of this study were to define the temporal and spatial infiltration of immune cell populations and their activation patterns in a murine cerebral ischemia-reperfusion injury model. Transient middle cerebral artery occlusion was induced for 1 hour followed by 12-hour to 7-day reperfusion in C57/BL6 mice. Immunohistochemistry and flow cytometry were used to quantify the infiltrating immune cell subsets. Accumulation of microglia and infiltration of the ischemic hemisphere by macrophages, lymphocytes, and dendritic cells (DCs) preceded the neutrophilic influx. DCs were found to increase 20-fold and constituted a substantial proportion of infiltrating cells. DCs exhibited a significant upregulation of major histocompatibility complex II and major histocompatibility complex II high-expressing DCs were found 100 times more abundant than in sham conditions. Upregulation of the costimulatory molecule CD80 was observed in DCs and microglial cells but did not further increase in major histocompatibility complex II high-expressing DCs. No lymphocyte activation was observed. Additionally, regulatory immune cells (natural killer T-cells, CD4(-)/CD8(-)T lymphocytes) cumulated in the ischemic hemisphere. This study provides a detailed analysis of the temporal dynamics of immune cell accumulation in a rodent stroke model. The peculiar activation pattern and massive increase of antigen-presenting cells in temporal conjunction with regulatory cells might provide additional insight into poststroke immune regulation.

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Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis.

Gianfranco Bazzoni, Elisabetta Dejana (2004)

Intercellular junctions mediate adhesion and communication between adjoining endothelial and epithelial cells. In the endothelium, junctional complexes comprise tight junctions, adherens junctions, and gap junctions. The expression and organization of these complexes depend on the type of vessels and the permeability requirements of perfused organs. Gap junctions are communication structures, which allow the passage of small molecular weight solutes between neighboring cells. Tight junctions serve the major functional purpose of providing a "barrier" and a "fence" within the membrane, by regulating paracellular permeability and maintaining cell polarity. Adherens junctions play an important role in contact inhibition of endothelial cell growth, paracellular permeability to circulating leukocytes and solutes. In addition, they are required for a correct organization of new vessels in angiogenesis. Extensive research in the past decade has identified several molecular components of the tight and adherens junctions, including integral membrane and intracellular proteins. These proteins interact both among themselves and with other molecules. Here, we review the individual molecules of junctions and their complex network of interactions. We also emphasize how the molecular architectures and interactions may represent a mechanistic basis for the function and regulation of junctions, focusing on junction assembly and permeability regulation. Finally, we analyze in vivo studies and highlight information that specifically relates to the role of junctions in vascular endothelial cells.

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Physiology and pathophysiology of matrix metalloproteases

T W Klein, J R Bischoff (2010)

Matrix metalloproteases (MMPs) comprise a family of enzymes that cleave protein substrates based on a conserved mechanism involving activation of an active site-bound water molecule by a Zn2+ ion. Although the catalytic domain of MMPs is structurally highly similar, there are many differences with respect to substrate specificity, cellular and tissue localization, membrane binding and regulation that make this a very versatile family of enzymes with a multitude of physiological functions, many of which are still not fully understood. Essentially, all members of the MMP family have been linked to disease development, notably to cancer metastasis, chronic inflammation and the ensuing tissue damage as well as to neurological disorders. This has stimulated a flurry of studies into MMP inhibitors as therapeutic agents, as well as into measuring MMP levels as diagnostic or prognostic markers. As with most protein families, deciphering the function(s) of MMPs is difficult, as they can modify many proteins. Which of these reactions are physiologically or pathophysiologically relevant is often not clear, although studies on knockout animals, human genetic and epigenetic, as well as biochemical studies using natural or synthetic inhibitors have provided insight to a great extent. In this review, we will give an overview of 23 members of the human MMP family and describe functions, linkages to disease and structural and mechanistic features. MMPs can be grouped into soluble (including matrilysins) and membrane-anchored species. We adhere to the ‘MMP nomenclature’ and provide the reader with reference to the many, often diverse, names for this enzyme family in the introduction.

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Author and article information

Contributors

Qianyi Huang: HQY0623@csu.edu.cn

Wei Zhong: zhongwei405@csu.edu.cn

Zhiping Hu: zhipinghu@csu.edu.cn

Xiangqi Tang: +86 13875807186 , txq6633@csu.edu.cn

Journal

Journal ID (nlm-ta): J Neuroinflammation

Journal ID (iso-abbrev): J Neuroinflammation

Title: Journal of Neuroinflammation

Publisher: BioMed Central (London )

ISSN (Electronic): 1742-2094

Publication date (Electronic): 20 December 2018

Publication date PMC-release: 20 December 2018

Publication date Collection: 2018

Volume: 15

Electronic Location Identifier: 348

Affiliations

ISNI 0000 0001 0379 7164, GRID grid.216417.7, Department of Neurology, The Second Xiangya Hospital, , Central South University, ; Renmin Road 139#, Changsha, 410011 Hunan China

Article

Publisher ID: 1387

DOI: 10.1186/s12974-018-1387-y

PMC ID: 6302517

PubMed ID: 30572925

SO-VID: 1950c3a8-10a3-4d5d-9098-7a9d9f21ed02

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 10 September 2018

Date accepted : 29 November 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: Grant no.81271298

Award Recipient : Xiangqi Tang

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ScienceOpen disciplines: Neurosciences

Keywords: ischemic stroke,cav-1,bbb permeability,neurogenesis,angiogenesis,neuroinflammation,apoptosis,oxidative stress

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ScienceOpen disciplines: Neurosciences

Keywords: ischemic stroke, cav-1, bbb permeability, neurogenesis, angiogenesis, neuroinflammation, apoptosis, oxidative stress

A review of the role of cav-1 in neuropathology and neural recovery after ischemic stroke

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Neuronal Signaling

Most cited references 126

Temporal and spatial dynamics of cerebral immune cell accumulation in stroke.

Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis.

Physiology and pathophysiology of matrix metalloproteases

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