Abstract
Abstract 146: Deficiency of Cystathionine beta Synthase Alters Blood Brain Barrier Integrity and Exacerbates Cerebral Ischemia Reperfusion Injury in Mice
Arteriosclerosis, thrombosis, and vascular biology, Vol.37(suppl_1)
05/2017
DOI: 10.1161/atvb.37.suppl_1.146
Abstract
Hyperhomocysteinemia is a risk factor for stroke; however the mechanisms by which elevated homocysteine leads to stroke are poorly defined. In a murine model of cystathionine beta synthase (CBS) deficiency, we investigated whether mild to severe elevation in plasma total homocysteine (tHcy) increases susceptibility to cerebral infarction and if this phenotype is associated with loss of blood brain barrier (BBB) integrity. We studied male
Cbs
-/- mice conditionally expressing a zinc-inducible mutated human
CBS
(I278T)
transgene along with
Cbs+/-
and
Cbs+/+
littermates at 10-14 weeks of age. The human transgene was allowed to express only until weaning to overcome the early mortality of
Cbs-/-
mice. Experimental stroke was induced with middle cerebral artery occlusion for one hour followed by 24 hours of reperfusion. TTC stained coronal sections were used to quantify the infarcted area. BBB integrity was assessed prior to injury using a standard Evan’s blue (EB) infusion method. Leakage of EB was quantified in brain homogenates and normalized to brain weight. Mild to severe increases in plasma tHcy were observed in
Cbs
+/- and
Cbs
-/- mice (6.1±0.3 and 309±18 μM, respectively) compared with
Cbs+/+
littermates (3.1±0.6 μM, P<0.01). Both
Cbs
+/- and
Cbs
-/- mice exhibited significant increases in infarct size following ischemia-reperfusion injury as compared to
Cbs+/+
mice (12.2±3% in
Cbs+/+
mice vs. 35.1±7.7% in
Cbs+/-
and 27.7±7.8% in
Cbs-/-
mice, P<0.05). A significant increase in EB extravasation was observed in
Cbs+/-
and
Cbs
-/- mice (3.8±0.8 and 4.8±0.2 μg/g, respectively) compared to
Cbs+/+
mice (1.7±0.4 μg/g, P<0.05). The similarity in extent of cerebral infarction observed in
Cbs+/-
and
Cbs-/-
mice suggests a threshold effect and that a mild increase in tHcy is enough to disrupt BBB integrity and produce a severe stroke phenotype in experimental murine models.
Details
- Title: Subtitle
- Abstract 146: Deficiency of Cystathionine beta Synthase Alters Blood Brain Barrier Integrity and Exacerbates Cerebral Ischemia Reperfusion Injury in Mice
- Creators
- Sean X Gu - University of IowaVijay Sonkar - University of IowaWarren D Kruger - Fox Chase Cancer CenterTeodoro Bottiglieri - Baylor UniversitySteven R Lentz - University of IowaSanjana Dayal - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.37(suppl_1)
- DOI
- 10.1161/atvb.37.suppl_1.146
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Language
- English
- Date published
- 05/2017
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine; Iowa Neuroscience Institute
- Record Identifier
- 9984363156702771
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