Brain-Heart Interaction After Stroke: Therapeutic Effects of Exosomes in Type 2 Diabetic Mice Subjected to Stroke

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Aim: Diabetes exacerbates post-stroke cardiac injury. We tested whether treatment with exosomes harvested from human umbilical cord blood derived CD133+/KDR+ cells (CD133+Exo) improves neurological, cognitive and cardiac functional outcome in type 2 diabetes mellitus (T2DM) stroke mice. Methods: Adult (3-4m), male, db/db (T2DM) mice were subjected to distal middle cerebral artery occlusion (dMCAo) and treated with PBS or CD133+Exo (3x10 , i.v.) at 3 days after stroke (n=8/group). Serum exosomal microRNA (miR) expression was measured. Echocardiography, neurological and cognitive tests were performed, and mice were sacrificed at 28 days after stroke. Results: 1) Compared to T2DM-control, T2DM-stroke mice exhibit significantly decreased left ventricular ejection fraction (LVEF: db/db: 67.6±0.6%, db/db-dMCAo: 60.6±1.9%, p<0.05), significant cardiomyocyte hypertrophy, interstitial fibrosis, and decreased capillary density in heart indicating that stroke in T2DM mice induces cardiac dysfunction at 28 days after stroke. 2) Serum exosomal miR29b and miR126 expression was significantly decreased in T2DM-stroke mice compared to T2DM-control mice. CD133+Exo contain high levels of miR126 and miR29b. 3) CD133+Exo treatment in T2DM-stroke mice significantly promotes neurological functional recovery (foot-fault test), significantly improves cognitive outcome (Morris water maze (MWM) test and odor test), and significantly improves cardiac function (LVEF: db/db-dMCAo: 60.6±1.9%, db/dbdMCAo+ CD133+Exo: 68.9±0.7%, p<0.05). 4) In T2DM-stroke mice with PBS or CD133+Exo treatment, cardiac function (LVEF) significantly correlates with cognitive outcome. 5) CD133+Exo treatment in T2DM-stroke mice significantly decreases myocardial fibrosis, decreases TGF-β and NOX2 expression, and increases heart tissue miR126 and miR29b expression, while decreasing expression of miR126 and miR29b target genes such as Spred-1 and DPP4. Conclusions: Stroke in T2DM mice induces significant cardiac dysfunction and CD133+Exo treatment improves neurological and cognitive outcome, and provides significant cardio-protection. The improvement in cardiac functional outcome highly correlates with cognitive functional recovery.



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