Endothelin-1-mediated cerebral ischemia in mice: early cellular events and the role of caspase-3.
Chesarahmia Dojo SoeandyFaraz SalmasiMaya LatifAndrew J EliaNan Ji SuoJeffrey T HendersonPublished in: Apoptosis : an international journal on programmed cell death (2020)
Over the past 30 years a number of animal models of cerebral ischemic injury have been developed. Middle cerebral artery occlusion (MCAO) in particular reproduces both ischemic and reperfusion elements and is widely utilized as a model of ischemic stroke in rodents. However substantial variability exists in this model even in clonal inbred mice due to stochastic elements of the cerebral vasculature. Models such as MCAO thus exhibit significant irreducible variabilities with respect to their zone of injury as well as inducing a sizable volume of injury to the cerebrum with damage to sub-cortical structures, conditions not typically seen for the majority of human clinical strokes. An alternative model utilizes endothelin-1 application focally to cerebral vasculature, resulting in an ischemic reperfusion injury which more closely mimics that seen in human clinical stroke. In order to further define this model we demonstrate that intra-cortical administration of ET-1 results in a highly reproducible pattern of tissue injury which is limited to the cerebral cortex, characterizing the early cellular and molecular events which occur during the first 24 h post-injury. In addition we demonstrate that caspase-3 is both necessary and sufficient to regulate a majority of cortical cell death observed during this period. The enhanced survival effects seen upon genetic deletion of caspase-3 appear to arise as a result of direct modification of cell autonomous PCD signaling as opposed to secondary effectors such as granulocyte infiltration or microglia activation. Taken together these findings detail the early mechanistic features regulating endothelin-1-mediated ischemic injury.
Keyphrases
- cerebral ischemia
- subarachnoid hemorrhage
- cell death
- brain injury
- blood brain barrier
- endothelial cells
- middle cerebral artery
- heart failure
- acute myocardial infarction
- atrial fibrillation
- cell proliferation
- adipose tissue
- high resolution
- acute coronary syndrome
- single cell
- inflammatory response
- dna methylation
- skeletal muscle
- gene expression
- peripheral blood
- acute ischemic stroke
- pluripotent stem cells
- spinal cord injury
- oxidative stress
- bone marrow
- neuropathic pain