Abstract
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 (ERK2wt) 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 (RKIPwt) and its phosphorylation-deficient mutant RKIPS153A, known inhibitors of the ERK1/2 signaling cascade. RKIPwt and RKIPS153A 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.
Highlights
Publisher’s Note: MDPI stays neutralCardiovascular diseases are the leading cause of mortality worldwide, especially ischemic disorders such as stroke, which are responsible for substantial mortality and morbidity rates [1]
We aimed to investigate the role of extracellular signal-regulated kinases 1 and 2 (ERK1/2) after acute cerebral ischemia in transgenic mice using constitutive overexpression of proteins that impact on ERK activation, i.e., mice that ubiquitously overexpress ERK2wt, RKIPwt, or RKIPS153A under the control of the “CAG” promoter [19,20]
We demonstrate that the ubiquitous overexpression of ERK2wt is detrimental in a model of ischemic stroke as it increases infarct size and neurological deficits after transient middle cerebral artery occlusion (tMCAO) by increasing disruption of the blood–brain barrier (BBB), the immune response, and a loss of neurons
Summary
Publisher’s Note: MDPI stays neutralCardiovascular diseases are the leading cause of mortality worldwide, especially ischemic disorders such as stroke, which are responsible for substantial mortality and morbidity rates [1]. It is of therapeutic interest to understand the mechanisms involved in brain damage due to ischemic stroke and to identify intervention strategies. ERK1/2 are ubiquitously expressed throughout the body and are part of the Raf/mitogen-activated protein kinase (MEK)/ERK1/2 signaling cascade [7]. Activation of this cascade is involved in proliferation, differentiation, cell death, and inflammation [5,6,8]. The impact of ERK1/2 signaling in stroke was analyzed using different MEK/ERK1/2 inhibitors [9,10] or by transient overexpression of the endogenous Raf-kinase inhibitor protein (RKIP) [11,12], or agents that stimulate the Raf/MEK/ERK1/2-cascade such as β-hydroxybutyrate [13]
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