TMEM16A Inhibition Preserves Blood–Brain Barrier Integrity After Ischemic Stroke

Abstract

The inflammatory response plays a pivotal role in Blood-Brain Barrier (BBB) destruction following ischemic brain injury. Enhanced leukocyte adhesion to vascular endothelial cells is an essential event in the inflammatory process. TMEM16A, a newly discovered protein regulating calcium-activated chloride channels, is widely expressed in eukaryotes. Recent studies have suggested that upregulated expression of TMEM16A is associated with the occurrence and development of many diseases. However, the role of TMEM16A in regulating BBB integrity after ischemic stroke has not been fully investigated. In this study, we found that TMEM16A is mainly expressed in brain endothelial cells and upregulated after ischemic stroke in the mouse brain. Caccinh-A01, an TMEM16A inhibitor that reduced its upregulation, attenuated brain infarct size and neurological deficits after ischemic stroke. ICAM-1 and MPO expression and BBB permeability were decreased after TMEM16A inhibitor administration. In addition, TMEM16A silencing rescued oxygen-glucose deprivation/reoxygenation (OGD/R)induced transendothelial permeability in vitro accompanied by decreased ICAM-1 expression and leukocyte adhesion. Furthermore, our mechanistic study showed that TMEM16A knockdown alleviated NF-κB activation and nuclear translocation, indicating that TMEM16A knockdown downregulated OGD/R-induced ICAM-1 expression in an NF-κB-dependent manner. Finally, NF-κB inhibitor treatment also alleviated OGD/ R-induced BBB permeability, confirming that activated NF-κB and increased ICAM-1 are essential factors involved in ischemia-induced BBB damage. Thus, our research provides a promising treatment strategy against BBB destruction after ischemic stroke, and TMEM16A may become a potential target for the treatment of ischemic stroke.

Ca2+-activated Cl− channel TMEM16A inhibition by cholesterol promotes angiogenesis in endothelial cells

“…Among various ion channels in endothelial cells, Ca 2+ -activated Cl − channel is expressed in endothelial cells [4] , [5] , and is implicated in regulating endothelial functions, including membrane potential control, Ca 2+ signaling regulation, and cell proliferation [4] , [6] . Since TMEM16A (anoctamin 1) was discovered as a Ca 2+ -activated Cl − channel in 2008 [7] , [8] , [9] , it has been found in many endothelial cells [10] , [11] , [12] , [13] . TMEM16A contributes to endothelial dysfunction in hypertension by promoting the generation of reactive oxygen species [10] .…”

Calcium-activated chloride channels: structure, properties, role in physiological and pathological processes

“…Недостаточная изученность роли TMEM16А в физиологических и патофизиологических процессах была продемонстрирована в 2019 году в работе Liu и соавт., где показана новая роль TMEM16А в разрушении гематоэнцефалического барьера при ишемическом инсульте. Было показано, что TMEM16A, в основном, экспрессируется в эндотелиальных клетках мозга и активируется после ишемического инсульта в мозге мышей, а CaCC inh -A01 (блокатор СаСС) уменьшает размер инфаркта мозга и неврологический дефицит после ишемического инсульта [171]. Таким образом, кальций-активируемые хлорные каналы являются новой и очень перспективной мишенью для терапии огромного ряда тяжёлых и до сих пор неизлечимых заболеваний [172].…”

KLF4 alleviates cerebral vascular injury by ameliorating vascular endothelial inflammation and regulating tight junction protein expression following ischemic stroke

“…CAMs play a crucial role to initiate inflammatory mechanisms soon after cerebral damage [25]. The activated NF-κB and increased CAMs such as ICAM-1 are essential factors involved in ischemia-induced BBB damage [26]. They promote migration of immune cells across the BBB within the cerebral parenchyma, which further exacerbates the brain tissue damage and leads to brain swelling and expansion of the infarction from the penumbra [5].…”