ERK1/2 Activity Is Critical for the Outcome of Ischemic Stroke.
Constanze SchanbacherMichael BieberYvonne ReindersDeya CherpokovaChristina TeichertBernhard NieswandtAlbert SickmannChristoph KleinschnitzFriederike LanghauserKristina LorenzPublished in: International journal of molecular sciences (2022)
Ischemic disorders are the leading cause of death worldwide. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are thought to affect the outcome of ischemic stroke. However, it is under debate whether activation or inhibition of ERK1/2 is beneficial. In this study, we report that the ubiquitous overexpression of wild-type ERK2 in mice (ERK2 wt ) is detrimental after transient occlusion of the middle cerebral artery (tMCAO), as it led to a massive increase in infarct volume and neurological deficits by increasing blood-brain barrier (BBB) leakiness, inflammation, and the number of apoptotic neurons. To compare ERK1/2 activation and inhibition side-by-side, we also used mice with ubiquitous overexpression of the Raf-kinase inhibitor protein (RKIP wt ) and its phosphorylation-deficient mutant RKIP S153A , known inhibitors of the ERK1/2 signaling cascade. RKIP wt and RKIP S153A attenuated ischemia-induced damages, in particular via anti-inflammatory signaling. Taken together, our data suggest that stimulation of the Raf/MEK/ERK1/2-cascade is severely detrimental and its inhibition is rather protective. Thus, a tight control of the ERK1/2 signaling is essential for the outcome in response to ischemic stroke.
Keyphrases
- signaling pathway
- cell proliferation
- pi k akt
- blood brain barrier
- wild type
- middle cerebral artery
- anti inflammatory
- cerebral ischemia
- atrial fibrillation
- oxidative stress
- transcription factor
- metabolic syndrome
- spinal cord
- machine learning
- high fat diet induced
- internal carotid artery
- coronary artery disease
- diabetic rats
- drug induced
- protein kinase