• Jingli Yang, M Hossein Noyan-Ashraf, Anja Meissner, Julia Voigtlaender-Bolz, Jeffrey T Kroetsch, Warren Foltz, David Jaffray, Amita Kapoor, Abdul Momen, Scott P Heximer, Hangjun Zhang, Matthijs van Eede, R Mark Henkelman, Stephen G Matthews, Darcy Lidington, Mansoor Husain, and Steffen-Sebastian Bolz.
• Department of Physiology, Heart and Stroke/Richard Lewar Centre of Excellence in Cardiovascular Research, University of Toronto, Ontario, Canada.
• Circulation. 2012 Jul 10; 126 (2): 196-206.

BackgroundHeart failure is associated with neurological deficits, including cognitive dysfunction. However, the molecular mechanisms underlying reduced cerebral blood flow in the early stages of heart failure, particularly when blood pressure is minimally affected, are not known.Methods And ResultsUsing a myocardial infarction model in mice, we demonstrate a tumor necrosis factor-α (TNFα)-dependent enhancement of posterior cerebral artery tone that reduces cerebral blood flow before any overt changes in brain structure and function. TNFα expression is increased in mouse posterior cerebral artery smooth muscle cells at 6 weeks after myocardial infarction. Coordinately, isolated posterior cerebral arteries display augmented myogenic tone, which can be fully reversed in vitro by the competitive TNFα antagonist etanercept. TNFα mediates its effect via a sphingosine-1-phosphate (S1P)-dependent mechanism, requiring sphingosine kinase 1 and the S1P(2) receptor. In vivo, sphingosine kinase 1 deletion prevents and etanercept (2-week treatment initiated 6 weeks after myocardial infarction) reverses the reduction of cerebral blood flow, without improving cardiac function.ConclusionsCerebral artery vasoconstriction and decreased cerebral blood flow occur early in an animal model of heart failure; these perturbations are reversed by interrupting TNFα/S1P signaling. This signaling pathway may represent a potential therapeutic target to improve cognitive function in heart failure.

43 keywords...

hide…