Diabetes Mellitus Aggravates Hemorrhagic Transformation after Ischemic Stroke via Mitochondrial Defects Leading to Endothelial Apoptosis
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{"title"=>"Diabetes mellitus aggravates hemorrhagic transformation after ischemic stroke via mitochondrial defects leading to endothelial apoptosis", "type"=>"journal", "authors"=>[{"first_name"=>"Keisuke", "last_name"=>"Mishiro", "scopus_author_id"=>"37021639200"}, {"first_name"=>"Takahiko", "last_name"=>"Imai", "scopus_author_id"=>"56638904600"}, {"first_name"=>"Sou", "last_name"=>"Sugitani", "scopus_author_id"=>"55178594200"}, {"first_name"=>"Akira", "last_name"=>"Kitashoji", "scopus_author_id"=>"55796699000"}, {"first_name"=>"Yukiya", "last_name"=>"Suzuki", "scopus_author_id"=>"7407202891"}, {"first_name"=>"Toshinori", "last_name"=>"Takagi", "scopus_author_id"=>"36657649100"}, {"first_name"=>"Huayue", "last_name"=>"Chen", "scopus_author_id"=>"8296506700"}, {"first_name"=>"Yasunori", "last_name"=>"Oumi", "scopus_author_id"=>"57194437472"}, {"first_name"=>"Kazuhiro", "last_name"=>"Tsuruma", "scopus_author_id"=>"6505831524"}, {"first_name"=>"Masamitsu", "last_name"=>"Shimazawa", "scopus_author_id"=>"6602683783"}, {"first_name"=>"Hideaki", "last_name"=>"Hara", "scopus_author_id"=>"56799750000"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"373772720", "sgr"=>"84929138393", "issn"=>"19326203", "pmid"=>"25133692", "scopus"=>"2-s2.0-84929138393", "doi"=>"10.1371/journal.pone.0103818", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)"}, "id"=>"6c389f3c-8526-31ef-8c92-b8e6f75059c7", "abstract"=>"Diabetes is a crucial risk factor for stroke and is associated with increased frequency and poor prognosis. Although endothelial dysfunction is a known contributor of stroke, the underlying mechanisms have not been elucidated. The aim of this study was to elucidate the mechanism by which chronic hyperglycemia may contribute to the worsened prognosis following stroke, especially focusing on mitochondrial alterations. We examined the effect of hyperglycemia on hemorrhagic transformation at 24 hours after middle cerebral artery occlusion (MCAO) in streptozotocin (STZ) -induced diabetic mice. We also examined the effects of high-glucose exposure for 6 days on cell death, mitochondrial functions and morphology in human brain microvascular endothelial cells (HBMVECs) or human endothelial cells derived from induced pluripotent stem cells (iCell endothelial cells). Hyperglycemia aggravated hemorrhagic transformation, but not infarction following stroke. High-glucose exposure increased apoptosis, capase-3 activity, and release of apoptosis inducing factor (AIF) and cytochrome c in HBMVECs as well as affected mitochondrial functions (decreased cell proliferation, ATP contents, mitochondrial membrane potential, and increased matrix metalloproteinase (MMP)-9 activity, but not reactive oxygen species production). Furthermore, morphological aberration of mitochondria was observed in diabetic cells (a great deal of fragmentation, vacuolation, and cristae disruption). A similar phenomena were seen also in iCell endothelial cells. In conclusion, chronic hyperglycemia aggravated hemorrhagic transformation after stroke through mitochondrial dysfunction and morphological alteration, partially via MMP-9 activation, leading to caspase-dependent apoptosis of endothelial cells of diabetic mice. Mitochondria-targeting therapy may be a clinically innovative therapeutic strategy for diabetic complications in the future.", "link"=>"http://www.mendeley.com/research/diabetes-mellitus-aggravates-hemorrhagic-transformation-after-ischemic-stroke-via-mitochondrial-defe", "reader_count"=>23, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>2, "Researcher"=>5, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>1, "Student > Master"=>2, "Student > Bachelor"=>6, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>2, "Researcher"=>5, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>1, "Student > Master"=>2, "Student > Bachelor"=>6, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>3, "Materials Science"=>1, "Medicine and Dentistry"=>9, "Agricultural and Biological Sciences"=>4, "Neuroscience"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Physics and Astronomy"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Materials Science"=>{"Materials Science"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>9}, "Neuroscience"=>{"Neuroscience"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>4}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Italy"=>1}, "group_count"=>2}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1641006"], "description"=>"<p>A: Cell proliferation (n = 7). B: ATP contents (n = 10). C: Mitochondrial membrane potential, determined by tetramethyl rhodamine methyl ester (TMRM) intensity (n = 10). The scale bar indicates 100 µm. D: reactive oxygen species (ROS) levels (n = 10). E: Binding of 4-hydroxy-2-nonenal (4-HNE), an indicator of lipoperoxidation by ROS. F: Enzymatic activities of MMP-2 and MMP-9 by gelatin zymography (n = 3). All data are expressed as mean ± SEM (shown as ratio to 5.5 mM). *P<0.05, **P<0.01 vs. 5.5 mM (Dunnet's test). HBMVECs, human brain microvascular endothelial cells.</p>", "links"=>[], "tags"=>["Endothelial Apoptosis Diabetes", "mitochondrial functions", "hbmvec", "diabetes Mellitus Aggravates Hemorrhagic Transformation", "reactive oxygen species production", "atp", "mcao", "mmp", "stroke", "aif", "stz", "hemorrhagic transformation"], "article_id"=>1143533, "categories"=>["Biological Sciences"], "users"=>["Keisuke Mishiro", "Takahiko Imai", "Sou Sugitani", "Akira Kitashoji", "Yukiya Suzuki", "Toshinori Takagi", "Huayue Chen", "Yasunori Oumi", "Kazuhiro Tsuruma", "Masamitsu Shimazawa", "Hideaki Hara"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103818.g003", "stats"=>{"downloads"=>1, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_chronic_high_glucose_exposure_on_mitochondrial_function_in_HBMVECs_/1143533", "title"=>"Effects of chronic high-glucose exposure on mitochondrial function in HBMVECs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-18 04:21:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1641005"], "description"=>"<p>A: Experimental protocol <i>in vitro</i>. B: Nuclear staining for Hoechst 33342. The number of cells exhibiting nuclear stain was counted (n = 10). The scale bar indicates 50 µm. C: Number of TUNEL-positive cells (n = 4). The scale bar indicates 100 µm. D: Caspase-3/7 activities (n = 10). E: Immunoblotting for Active Caspase-3. F: Immunoblotting for Caspase-7. G: Release of apoptosis inducing factor (AIF) and cytochrome <i>c</i> (Cyto <i>c</i>) into cytosol, and transit into the nucleus (n = 3). All data are expressed as mean ± SEM (shown as ratio to 5.5 mM). *P<0.05, **P<0.01 vs. 5.5 mM (Dunnet's test). HBMVECs, human brain microvascular endothelial cells.</p>", "links"=>[], "tags"=>["Endothelial Apoptosis Diabetes", "mitochondrial functions", "hbmvec", "diabetes Mellitus Aggravates Hemorrhagic Transformation", "reactive oxygen species production", "atp", "mcao", "mmp", "stroke", "aif", "stz", "hemorrhagic transformation"], "article_id"=>1143532, "categories"=>["Biological Sciences"], "users"=>["Keisuke Mishiro", "Takahiko Imai", "Sou Sugitani", "Akira Kitashoji", "Yukiya Suzuki", "Toshinori Takagi", "Huayue Chen", "Yasunori Oumi", "Kazuhiro Tsuruma", "Masamitsu Shimazawa", "Hideaki Hara"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103818.g002", "stats"=>{"downloads"=>2, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_chronic_high_glucose_exposure_on_apoptotic_cell_death_in_HBMVECs_/1143532", "title"=>"Effects of chronic high-glucose exposure on apoptotic cell death in HBMVECs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-18 04:21:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1641010", "https://ndownloader.figshare.com/files/1641011", "https://ndownloader.figshare.com/files/1641012", "https://ndownloader.figshare.com/files/1641013", "https://ndownloader.figshare.com/files/1641014"], "description"=>"<div><p>Diabetes is a crucial risk factor for stroke and is associated with increased frequency and poor prognosis. Although endothelial dysfunction is a known contributor of stroke, the underlying mechanisms have not been elucidated. The aim of this study was to elucidate the mechanism by which chronic hyperglycemia may contribute to the worsened prognosis following stroke, especially focusing on mitochondrial alterations. We examined the effect of hyperglycemia on hemorrhagic transformation at 24 hours after middle cerebral artery occlusion (MCAO) in streptozotocin (STZ) -induced diabetic mice. We also examined the effects of high-glucose exposure for 6 days on cell death, mitochondrial functions and morphology in human brain microvascular endothelial cells (HBMVECs) or human endothelial cells derived from induced pluripotent stem cells (iCell endothelial cells). Hyperglycemia aggravated hemorrhagic transformation, but not infarction following stroke. High-glucose exposure increased apoptosis, capase-3 activity, and release of apoptosis inducing factor (AIF) and cytochrome c in HBMVECs as well as affected mitochondrial functions (decreased cell proliferation, ATP contents, mitochondrial membrane potential, and increased matrix metalloproteinase (MMP)-9 activity, but not reactive oxygen species production). Furthermore, morphological aberration of mitochondria was observed in diabetic cells (a great deal of fragmentation, vacuolation, and cristae disruption). A similar phenomena were seen also in iCell endothelial cells. In conclusion, chronic hyperglycemia aggravated hemorrhagic transformation after stroke through mitochondrial dysfunction and morphological alteration, partially via MMP-9 activation, leading to caspase-dependent apoptosis of endothelial cells of diabetic mice. Mitochondria-targeting therapy may be a clinically innovative therapeutic strategy for diabetic complications in the future.</p></div>", "links"=>[], "tags"=>["Endothelial Apoptosis Diabetes", "mitochondrial functions", "hbmvec", "diabetes Mellitus Aggravates Hemorrhagic Transformation", "reactive oxygen species production", "atp", "mcao", "mmp", "stroke", "aif", "stz", "hemorrhagic transformation"], "article_id"=>1143537, "categories"=>["Biological Sciences"], "users"=>["Keisuke Mishiro", "Takahiko Imai", "Sou Sugitani", "Akira Kitashoji", "Yukiya Suzuki", "Toshinori Takagi", "Huayue Chen", "Yasunori Oumi", "Kazuhiro Tsuruma", "Masamitsu Shimazawa", "Hideaki Hara"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0103818.s001", "https://dx.doi.org/10.1371/journal.pone.0103818.s002", "https://dx.doi.org/10.1371/journal.pone.0103818.s003", "https://dx.doi.org/10.1371/journal.pone.0103818.s004", "https://dx.doi.org/10.1371/journal.pone.0103818.s005"], "stats"=>{"downloads"=>13, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Diabetes_Mellitus_Aggravates_Hemorrhagic_Transformation_after_Ischemic_Stroke_via_Mitochondrial_Defects_Leading_to_Endothelial_Apoptosis_/1143537", "title"=>"Diabetes Mellitus Aggravates Hemorrhagic Transformation after Ischemic Stroke via Mitochondrial Defects Leading to Endothelial Apoptosis", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-08-18 04:21:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1641008"], "description"=>"<p>A: Characterization of iCell endothelial cells by immunostaining of CD31, a marker of endothelial cells. The scale bar indicates 20 µm. B: Temporal changes of cell proliferation, assessed at 1, 3, and 6 days after the onset of high-glucose exposure (n = 9 or 10). C: Nuclear staining for Hoechst 33342. The number of cells exhibiting nuclear stain was counted (n = 10). The scale bar indicates 50 µm. D: Number of TUNEL-positive cells (n = 4). The scale bar indicates 100 µm. All data are expressed as mean ± SEM (shown as percentage of 5.5 mM). *P<0.05, **P<0.01 vs. 5.5 mM (Tukey's test or Dunnet's test).</p>", "links"=>[], "tags"=>["Endothelial Apoptosis Diabetes", "mitochondrial functions", "hbmvec", "diabetes Mellitus Aggravates Hemorrhagic Transformation", "reactive oxygen species production", "atp", "mcao", "mmp", "stroke", "aif", "stz", "hemorrhagic transformation"], "article_id"=>1143535, "categories"=>["Biological Sciences"], "users"=>["Keisuke Mishiro", "Takahiko Imai", "Sou Sugitani", "Akira Kitashoji", "Yukiya Suzuki", "Toshinori Takagi", "Huayue Chen", "Yasunori Oumi", "Kazuhiro Tsuruma", "Masamitsu Shimazawa", "Hideaki Hara"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103818.g005", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_chronic_high_glucose_exposure_on_human_endothelial_cells_derived_from_iPS_cells_/1143535", "title"=>"Effects of chronic high-glucose exposure on human endothelial cells derived from iPS cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-18 04:21:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1641009"], "description"=>"<p>Hyperglycemia increases the activity of MMP-9 in an ROS-independent manner, which promotes the opening of mitochondrial permeability transition pores (mitochondrial depolarization; Δ<b>ψ</b><sub>m</sub> ↓↓). The mitochondria that have lost normal function can no longer produce ATP, and emit various pro-apoptotic factors, such as AIF and cytochrome c into the cytosol. These factors subsequently activate caspase-3 and induce apoptotic cell death in HBMVECs. On the other hand, functional failure leads to morphological alteration of mitochondria, (fragmentation, vacuolation, cristae disruption). Eventually, both of these functional and morphological disturbances result in the aggravation of hemorrhagic transformation after ischemic stroke.</p>", "links"=>[], "tags"=>["Endothelial Apoptosis Diabetes", "mitochondrial functions", "hbmvec", "diabetes Mellitus Aggravates Hemorrhagic Transformation", "reactive oxygen species production", "atp", "mcao", "mmp", "stroke", "aif", "stz", "hemorrhagic transformation"], "article_id"=>1143536, "categories"=>["Biological Sciences"], "users"=>["Keisuke Mishiro", "Takahiko Imai", "Sou Sugitani", "Akira Kitashoji", "Yukiya Suzuki", "Toshinori Takagi", "Huayue Chen", "Yasunori Oumi", "Kazuhiro Tsuruma", "Masamitsu Shimazawa", "Hideaki Hara"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103818.g006", "stats"=>{"downloads"=>4, "page_views"=>304, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Diagram_illustrating_the_postulated_mechanism_through_which_hyperglycemia_aggravates_hemorrhagic_transformation_after_ischemic_stroke_/1143536", "title"=>"Diagram illustrating the postulated mechanism through which hyperglycemia aggravates hemorrhagic transformation after ischemic stroke.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-18 04:21:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1641007"], "description"=>"<p>A: Mitochondrial shapes were identified by immunostaining of HSP60, a marker of normal mitochondria. The scale bars indicate 20 µm in upper, and 5 µm in lower pictures, respectively. B: Accumulation of HSP60 in mitochondria, which reflects the quantitative alteration of mitochondria (n = 3). Data are expressed as mean ± SEM. C: More detailed morphological alteration of mitochondria by transmission electron microscopy (TEM). The scale bars indicate 1 µm (left panels) and 500 nm (right panels), respectively. Abnormal mitochondria, described as absolute disintegration of normal mitochondrial structure, were counted (shown as percentage of total mitochondria) (5.5 mM, n = 11; 16.5 mM, n = 15; 30 mM, n = 11).</p>", "links"=>[], "tags"=>["Endothelial Apoptosis Diabetes", "mitochondrial functions", "hbmvec", "diabetes Mellitus Aggravates Hemorrhagic Transformation", "reactive oxygen species production", "atp", "mcao", "mmp", "stroke", "aif", "stz", "hemorrhagic transformation"], "article_id"=>1143534, "categories"=>["Biological Sciences"], "users"=>["Keisuke Mishiro", "Takahiko Imai", "Sou Sugitani", "Akira Kitashoji", "Yukiya Suzuki", "Toshinori Takagi", "Huayue Chen", "Yasunori Oumi", "Kazuhiro Tsuruma", "Masamitsu Shimazawa", "Hideaki Hara"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103818.g004", "stats"=>{"downloads"=>4, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_chronic_high_glucose_exposure_on_morphological_alteration_of_mitochondria_in_HBMVECs_/1143534", "title"=>"Effects of chronic high-glucose exposure on morphological alteration of mitochondria in HBMVECs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-18 04:21:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1641004"], "description"=>"<p>A: Experimental protocol <i>in vivo</i>. A total of 44 mice were evaluated (Sham; n = 5, Control; n = 18, Diabetes; n = 21). STZ, streptozotocin; MCAO, middle cerebral artery occlusion. B: Changes in body weight after reperfusion. *P<0.05 vs. Sham (Student's <i>t</i>-test). C: Blood glucose levels at 21 h after reperfusion. **P<0.01 vs. Control (Student's <i>t</i>-test). D: Mortality, determined at 21 h after the reperfusion (Chi-square test test). E: Infarct area and volume at 21 h after the reperfusion (Control; n = 7, Diabetes; n = 6). Representative coronal sections were located 1 mm posterior to bregma. TTC-stained coronal sections show infarct tissues (pale unstained region). F: Hemorrhagic volume at 21 h after the reperfusion (Control; n = 11, Diabetes; n = 12). *P<0.05 vs. Control (Student's <i>t</i>-test). Representative images of whole brains and coronal sections located in 1 mm posterior to the bregma, respectively. All data are expressed as mean ± SEM.</p>", "links"=>[], "tags"=>["Endothelial Apoptosis Diabetes", "mitochondrial functions", "hbmvec", "diabetes Mellitus Aggravates Hemorrhagic Transformation", "reactive oxygen species production", "atp", "mcao", "mmp", "stroke", "aif", "stz", "hemorrhagic transformation"], "article_id"=>1143531, "categories"=>["Biological Sciences"], "users"=>["Keisuke Mishiro", "Takahiko Imai", "Sou Sugitani", "Akira Kitashoji", "Yukiya Suzuki", "Toshinori Takagi", "Huayue Chen", "Yasunori Oumi", "Kazuhiro Tsuruma", "Masamitsu Shimazawa", "Hideaki Hara"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103818.g001", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_chronic_hyperglycemia_on_acute_ischemic_stroke_in_mice_/1143531", "title"=>"Effects of chronic hyperglycemia on acute ischemic stroke in mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-18 04:21:52"}

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