ABSTRACT
BAK is a pro-apoptotic BCL-2 family protein that localizes to mitochondria. Here we evaluate the function of BAK in several mouse models of neuronal injury including neuronotropic Sindbis virus infection, Parkinson's disease, ischemia/stroke, and seizure. BAK promotes or inhibits neuronal death depending on the specific death stimulus, neuron subtype, and stage of postnatal development. BAK protects neurons from excitotoxicity and virus infection in the hippocampus. As mice mature, BAK is converted from anti- to pro-death function in virus-infected spinal cord neurons. In addition to regulating cell death, BAK also protects mice from kainate-induced seizures, suggesting a possible role in regulating synaptic activity. BAK can alter neurotransmitter release in a direction consistent with its protective effects on neurons and mice. These findings suggest that BAK inhibits cell death by modifying neuronal excitability.
Subject(s)
Apoptosis/genetics , Central Nervous System Diseases/metabolism , Central Nervous System/metabolism , Membrane Proteins/metabolism , Neurons/metabolism , Synaptic Transmission/genetics , Age Factors , Animals , Animals, Newborn , Central Nervous System/physiopathology , Central Nervous System/virology , Central Nervous System Diseases/genetics , Central Nervous System Viral Diseases/genetics , Central Nervous System Viral Diseases/metabolism , Disease Models, Animal , Epilepsy/genetics , Epilepsy/metabolism , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/genetics , Genetic Vectors/genetics , Hippocampus/metabolism , Hippocampus/physiopathology , Hippocampus/virology , Kainic Acid , Male , Membrane Proteins/genetics , Mice , Mice, Knockout , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/metabolism , Neurons/pathology , Neurons/virology , Neurotoxins/genetics , Neurotoxins/metabolism , Protein Structure, Tertiary/genetics , Sindbis Virus/genetics , Stroke/genetics , Stroke/metabolism , Synaptic Transmission/drug effects , bcl-2 Homologous Antagonist-Killer ProteinABSTRACT
BACKGROUND: Iron deficiency (ID) results in ventricular hypertrophy, believed to involve sympathetic stimulation. We hypothesized that with ID 1) intravenous norepinephrine would alter heart rate (HR) and contractility, 2) abdominal aorta would be larger and more distensible, and 3) the beta-blocker propanolol would reduce hypertrophy. METHODS: 1) 30 CD rats were fed an ID or replete diet for 1 week or 1 month. Norepinephrine was infused via jugular vein; pressure was monitored at carotid artery. Saline infusions were used as a control. The pressure trace was analyzed for HR, contractility, systolic and diastolic pressures. 2) Abdominal aorta catheters inflated the aorta, while digital microscopic images were recorded at stepwise pressures to measure arterial diameter and distensibility. 3) An additional 10 rats (5 ID, 5 control) were given a daily injection of propanolol or saline. After 1 month, the hearts were excised and weighed. RESULTS: Enhanced contractility, but not HR, was associated with ID hypertrophic hearts. Systolic and diastolic blood pressures were consistent with an increase in arterial diameter associated with ID. Aortic diameter at 100 mmHg and distensibility were increased with ID. Propanolol was associated with an increase in heart to body mass ratio. CONCLUSIONS: ID cardiac hypertrophy results in an increased inotropic, but not chronotropic response to the sympathetic neurotransmitter, norepinephrine. Increased aortic diameter is consistent with a flow-dependent vascular remodeling; increased distensibility may reflect decreased vascular collagen content. The failure of propanolol to prevent hypertrophy suggests that ID hypertrophy is not mediated via beta-adrenergic neurotransmission.
