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Aging and disease    2016, Vol. 7 Issue (1) : 14-27     DOI: 10.14336/AD.2015.0906
Original Article |
Mitochondrial Impairment in Cerebrovascular Endothelial Cells is Involved in the Correlation between Body Temperature and Stroke Severity
Hu Heng1,2, N. Doll Danielle1, Sun Jiahong1, E. Lewis Sara1, H. Wimsatt Jeffrey3, J. Kessler Matthew4, W. Simpkins James1,2, Ren Xuefang1,2,*
1 Department of Physiology and Pharmacology,
2 Experimental Stroke Core, Center for Basic and Translational Stroke Research,
3 Department of Medicine,
4 Office of Laboratory Animal Resources, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, West Virginia, 26506 USA
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Abstract  

Stroke is the second leading cause of death worldwide. The prognostic influence of body temperature on acute stroke in patients has been recently reported; however, hypothermia has confounded experimental results in animal stroke models. This work aimed to investigate how body temperature could prognose stroke severity as well as reveal a possible mitochondrial mechanism in the association of body temperature and stroke severity. Lipopolysaccharide (LPS) compromises mitochondrial oxidative phosphorylation in cerebrovascular endothelial cells (CVECs) and worsens murine experimental stroke. In this study, we report that LPS (0.1 mg/kg) exacerbates stroke infarction and neurological deficits, in the mean time LPS causes temporary hypothermia in the hyperacute stage during 6 hours post-stroke. Lower body temperature is associated with worse infarction and higher neurological deficit score in the LPS-stroke study. However, warming of the LPS-stroke mice compromises animal survival. Furthermore, a high dose of LPS (2 mg/kg) worsens neurological deficits, but causes persistent severe hypothermia that conceals the LPS exacerbation of stroke infarction. Mitochondrial respiratory chain complex I inhibitor, rotenone, replicates the data profile of the LPS-stroke study. Moreover, we have confirmed that rotenone compromises mitochondrial oxidative phosphorylation in CVECs. Lastly, the pooled data analyses of a large sample size (n=353) demonstrate that stroke mice have lower body temperature compared to sham mice within 6 hours post-surgery; the body temperature is significantly correlated with stroke outcomes; linear regression shows that lower body temperature is significantly associated with higher neurological scores and larger infarct volume. We conclude that post-stroke body temperature predicts stroke severity and mitochondrial impairment in CVECs plays a pivotal role in this hypothermic response. These novel findings suggest that body temperature is prognostic for stroke severity in experimental stroke animal models and may have translational significance for clinical stroke patients - targeting endothelial mitochondria may be a clinically useful approach for stroke therapy.

Keywords Hypothermia      Mitochondria      Stroke      Impairment      Endothelial Cells      Body Temperature      Severity     
Corresponding Authors: Ren Xuefang   
About author:

These authors equally contribute this work

Issue Date: 01 February 2016
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Hu Heng
N. Doll Danielle
Sun Jiahong
E. Lewis Sara
H. Wimsatt Jeffrey
J. Kessler Matthew
W. Simpkins James
Ren Xuefang
Cite this article:   
Hu Heng,N. Doll Danielle,Sun Jiahong, et al. Mitochondrial Impairment in Cerebrovascular Endothelial Cells is Involved in the Correlation between Body Temperature and Stroke Severity[J]. Aging and disease, 2016, 7(1): 14-27.
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http://www.aginganddisease.org/EN/10.14336/AD.2015.0906     OR     http://www.aginganddisease.org/EN/Y2016/V7/I1/14
Figure 1.  Low-dose LPS causes temporary hypothermia, and the body temperature is correlated with stroke outcomes. (A) Scheme of the experimental design. LPS (0.1 mg/kg, i.p.) or vehicle (saline, i.p.) was administered 30 min prior to right tMCAO (30 min occlusion) or sham and 48 hour reperfusion was performed. (B) Representative TTC-stained coronal sections from mice treated with vehicle or LPS (0.1 mg/kg), followed by 30 min tMCAO and 48 hours reperfusion. (C) Neurological deficits at 6 hours after tMCAO. Vehicle=18, LPS=23; data are expressed as mean ± S.D. ****, P<0.0001; Student’s t test. (D) Body temperature was recorded pre-treatment (PT), pre-surgery (PS), during surgery (S) and at 6, 12, 18, 24 and 48 hours. Data are expressed as mean ± S.D.; ****, P<0.0001; 2-way ANOVA followed by post-hoc Sidak’s multiple comparisons test. (E) Body temperature at 6 hours post-tMCAO is correlated with % cortex, striatum, and hemisphere infarction in 14 mice of the LPS (0.1 mg/kg) cohort of stroke study. (F) Body temperature at 6 hours post-tMCAO is correlated with neurologicial score in 41 mice of the LPS (0.1 mg/kg) cohort of stroke study.
Figure 2.  Rewarming worsens LPS-stroke mice and compromises animal survival. (A) External warming worsened neurological deficits of LPS-tMCAO mice at 6 hours reperfusion. Room temperature (RT) n = 23, 37°C warm blanket (WB) n= 6; data are expressed as mean ± S.D. ***, P<0.001; Student’s t test. (B) External warming compromised survival of LPS-tMCAO mice. LPS (0.1 mg/kg, ip) was administered prior to right tMCAO (30 min occlusion). Post-stroke mice were housed at room temperature (RT, n=23) or placed on warm blanket (37°C, n=6). Chi square was used for statistical analysis of the survival rate.
Figure 3.  High-dose LPS causes persistent hypothermia, worsens neurological deficits and results in immatured brain infarction. (A) Scheme of the experimental design. LPS (2 mg/kg, i.p.) or vehicle (saline, i.p.) was administered 30 min prior to right tMCAO (30 min occlusion) and 24 hour reperfusion was performed. (B) Neurological deficits at 24 hours after tMCAO. N=4 per group; data are expressed as mean ± S.D. *, P<0.05; Student’s t test. (C) Representative TTC-stained coronal sections from mice treated with vehicle or LPS (2 mg/kg), followed by 30 min tMCAO and 24 hours reperfusion. Blue arrow indicated immatured infarction by TTC-staining. (D) Body temperature was recorded pre-treatment (PT), pre-surgery (PS), during surgery (S) and at 6, 12, 18 and 24 hours. Data are expressed as mean ± S.D.; ****, P<0.0001; 2-way ANOVA followed by post-hoc Sidak’s multiple comparisons test.
Figure 4.  Rotenone decreases body temperature dose-dependently. (A) Scheme of the experimental design. Rotenone (i.p.) or vehicle (saline, i.p.) was administered and rectal temperature was recorded prior to treatment (PT), and at 6 and 24 hours. (B) Rotenone decreased rectal temperature in a dose-dependent manner. Data are expressed as mean ± S.D.; *, P<0.05, ****, P<0.0001; 2-way ANOVA followed by post-hoc Sidak’s multiple comparisons test.
Figure 5.  Low-dose rotenone causes hypothermia, and body temperature is correlated with acute stroke outcomes in mice. (A) Scheme of the experimental design. Rotenone (1 mg/kg, i.p.) or vehicle (saline, i.p.) was administered 30 min prior to right tMCAO (60 min occlusion) and 24 hour reperfusion was performed. (B) Representative TTC-stained coronal sections from mice treated with vehicle or rotenone (1 mg/kg), followed by 60 min tMCAO and 24 hours reperfusion. (C) Neurological deficits at 24 hours after tMCAO. N=12 per group; data are expressed as mean ± S.D. ****, P<0.0001; Student’s t test. (D) Body temperature was recorded pre-treatment (PT), pre-surgery (PS), during surgery (S) and at 6 and 24 hours. Data are expressed as mean ± S.D.; ****, P<0.0001; 2-way ANOVA followed by post-hoc Sidak’s multiple comparisons test. (E) Body temperature is correlated with neurologicial score in 24 mice of rotenone (1 mg/kg) cohort of stroke study. (F) Body temperature is correlated with % cortex infarction, striatum infarction, and hemisphere infarction in 16 mice in the rotenone (1 mg/kg) cohort of stroke study.
Figure 6.  High-dose rotenone causes persistent hypothermia, worsens neurological deficits, and results in immatured brain infarction. (A) Scheme of the experimental design. Rotenone (4 mg/kg, i.p.) or vehicle (saline, i.p.) was administered 30 min prior to right tMCAO (30 min occlusion) and 24 hour reperfusion was performed. (B) Neurological deficits at 24 hours after tMCAO. N=4 per group; data are expressed as mean ± S.D. **, P<0.01; Student’s t test. (C) Representative TTC-stained coronal sections from mice treated with vehicle or rotenone (4 mg/kg), followed by 30 min tMCAO and 24 hours reperfusion. Blue arrow indicates immature infarction from TTC staining. (D) Rectal temperature was recorded pre-treatment (PT), pre-surgery (PS), during surgery (S) and at 6 and 24 hours. Data are expressed as mean ± S.D.; ****, P<0.0001, ***, P<0.001; 2-way ANOVA followed by post-hoc Sidak’s multiple comparisons test.
Figure 7.  Rotenone compromises mitochondrial function in cultured cerebral vascular endothelial cells. (A) Raw data of oxgen consumption rate (OCR) determinied by the Seahorse XF96e analyzer. Cultured cerebral vascular endothelial cells (bEnd3. cell line) were incubated with various concentration of rotenone for 24 hours then OCR was determined upon sequential exposure to oligomycin, FCCP, and rotenone/antimycin. (B) Analysis of the Seahorse data. Rotenone decreased basal respiration, oligomycin-sensitive ATP production, maximal respiration in the presence of FCCP, and spare capacity of cerebral vascular endothelial cells in a dose-dependent manner. N = 4 per group; *, P<0.05; **, P<0.01; ***, P<0.001; ****, P<0.0001. One-way ANOVA followed by post-hoc Tukey’s test was used for statistical analysis.
Figure 8.  The relationship of body temperature and stroke outcomes in murine experimental stroke. (A) Stroke decreased body temperature. Rectal temperature was recorded pre-surgery (PS), during surgery (S), and within 6 hours post-surgery. Data are presented as mean ± S.D.; 2-way ANOVA followed by post-hoc Sidak's multiple comparisons test. ****, P<0.0001. (B) Body temperature is correlated with neurological score in 311 mice. (C) Body temperature is correlated with % cortex infarction, striatum infarction, and hemisphere infarction in 162 mice.
Figure 9.  Endothelial mitochondria and hypothermia are engaged in stroke outcomes. Stroke, LPS or rotenone compromises endothelial mitochondria in the acute stage. The mitochondrial impairment increases BBB permeability and brain edema, further worsens stroke outcomes. The mitochondrial impairment also leads to hypothermia, which is neuroprotective and protects stroke outcomes. Hypothermia is indicative of the mitochondrial capacity and therefore has prognostic effect on stroke outcomes.
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