ClC-5 knockout mitigates angiotensin II-induced hypertension and endothelial dysfunction.

Aims: Impairment of nitric oxide (NO) production is a major cause of endothelial dysfunction and hypertension. ClC-5 Cl channel is abundantly expressed in the vascular endothelium. However, it remains unclear how it regulates endothelial function.

Vascular smooth muscle-specific LRRC8A knockout ameliorates angiotensin II-induced cerebrovascular remodeling by inhibiting the WNK1/FOXO3a/MMP signaling pathway.

Hypertensive cerebrovascular remodeling involves the enlargement of vascular smooth muscle cells (VSMCs), which activates volume-regulated Cl channels (VRCCs). The leucine-rich repeat-containing family 8 A (LRRC8A) has been shown to be the molecular identity of VRCCs. However, its role in vascular remodeling during hypertension is unclear.

Increased intracellular Cl concentration mediates neutrophil extracellular traps formation in atherosclerotic cardiovascular diseases.

Neutrophil extracellular traps (NETs) play crucial roles in atherosclerotic cardiovascular diseases such as acute coronary syndrome (ACS). Our preliminary study shows that oxidized low-density lipoprotein (oxLDL)-induced NET formation is accompanied by an elevated intracellular Cl concentration ([Cl]) and reduced cystic fibrosis transmembrane conductance regulator (CFTR) expression in freshly isolated human blood neutrophils. Herein we investigated whether and how [Cl] regulated NET formation in vitro and in vivo.

CFTR Suppresses Neointimal Formation Through Attenuating Proliferation and Migration of Aortic Smooth Muscle Cells.

Cystic fibrosis transmembrane conductance regulator (CFTR) plays important roles in arterial functions and the fate of cells. To further understand its function in vascular remodeling, we examined whether CFTR directly regulates platelet-derived growth factor-BB (PDGF-BB)-stimulated vascular smooth muscle cells (VSMCs) proliferation and migration, as well as the balloon injury-induced neointimal formation. The CFTR adenoviral gene delivery was used to evaluate the effects of CFTR on neointimal formation in a rat model of carotid artery balloon injury.

Platelet CFTR inhibition enhances arterial thrombosis via increasing intracellular Cl concentration and activation of SGK1 signaling pathway.

Platelet hyperactivity is essential for thrombus formation in coronary artery diseases (CAD). Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients with cystic fibrosis elevates intracellular Cl levels ([Cl]) and enhanced platelet hyperactivity. In this study, we explored whether alteration of [Cl] has a pathological role in regulating platelet hyperactivity and arterial thrombosis formation.

Blockade of TMEM16A protects against renal fibrosis by reducing intracellular Cl concentration.

Background And Purpose: Renal fibrosis is the final common outcome in most forms of chronic kidney disease (CKD). However, the underlying causal mechanisms remain obscure. The present study examined whether transmembrane member 16A (TMEM16A), a Ca -activated chloride channel, contributes to the progression of renal fibrosis.

LRRC8A is essential for volume-regulated anion channel in smooth muscle cells contributing to cerebrovascular remodeling during hypertension.

Objectives: Recent studies revealed LRRC8A to be an essential component of volume-regulated anion channel (VRAC), which regulates cellular volume homeostasis. However, evidence for the contribution of LRRC8A-dependent VRAC activity in vascular smooth muscle cells (VSMCs) is still lacking, and the relevant functional role of LRRC8A in VSMCs remains unknown. The primary goal of this study was to elucidate the role of LRRC8A in VRAC activity in VSMCs and the functional role of LRRC8A in cerebrovascular remodeling during hypertension.

SGK1 mediates hypotonic challenge-induced proliferation in basilar artery smooth muscle cells via promoting CREB signaling pathway.

Hypotonic stimulus enlarges cell volume and increased cell proliferation with the exact mechanisms unknown. Glucocorticoid-induced kinase-1 (SGK1) is a serine/threonine kinase that can be regulated by osmotic pressure. We have revealed that SGK1 was activated by hypotonic solution-induced lowering of intracellular Cl concentration.

TMEM16A ameliorates vascular remodeling by suppressing autophagy via inhibiting Bcl-2-p62 complex formation.

: Transmembrane member 16A (TMEM16A) is a component of calcium-activated chloride channels that regulate vascular smooth muscle cell (SMC) proliferation and remodeling. Autophagy, a highly conserved cellular catabolic process in eukaryotes, exerts important physiological functions in vascular SMCs. In the current study, we investigated the relationship between TMEM16A and autophagy during vascular remodeling.

SGK1 mediates the hypotonic protective effect against HO-induced apoptosis of rat basilar artery smooth muscle cells by inhibiting the FOXO3a/Bim signaling pathway.

Serum- and glucocorticoid-inducible kinease-1 (SGK1) is a serine/threonine kinase regulated by hypotonic stimuli, which is involved in regulation of cell cycle and apoptosis. Our previous study shows that activation of volume-regulated Cl channels (VRCCs) protects rat basilar artery smooth muscle cells (BASMCs) against hydrogen peroxide (HO)-induced apoptosis. In the present study, we investigated whether SGK1 was involved in the protective effect of VRCCs in BASMCs.

Endophilin A2 regulates calcium-activated chloride channel activity via selective autophagy-mediated TMEM16A degradation.

TMEM16A Ca-activated chloride channel (CaCC) plays an essential role in vascular homeostasis. In this study we investigated the molecular mechanisms underlying downregulation of TMEM16A CaCC activity during hypertension. In cultured basilar artery smooth muscle cells (BASMCs) isolated from 2k2c renohypertesive rats, treatment with angiotensin II (0.

Smooth muscle-specific TMEM16A expression protects against angiotensin II-induced cerebrovascular remodeling via suppressing extracellular matrix deposition.

Cerebrovascular remodeling is the leading factor for stroke and characterized by increased extracellular matrix deposition, migration and proliferation of vascular smooth muscle cells, and inhibition of their apoptosis. TMEM16A is an important component of Ca-activated Cl channels. Previously, we showed that downregulation of TMEM16A in the basilar artery was negatively correlated with cerebrovascular remodeling during hypertension.

Clcn3 deficiency ameliorates high-fat diet-induced obesity and adipose tissue macrophage inflammation in mice.

Obesity induces accumulation of adipose tissue macrophages (ATMs) and ATM-driven inflammatory responses that promote the development of glucose and lipid metabolism disorders. ClC-3 chloride channel/antiporter, encoded by the Clcn3, is critical for some basic cellular functions. Our previous work has shown significant alleviation of type 2 diabetes in Clcn3 knockout (Clcn3) mice.

ClC-3 promotes angiotensin II-induced reactive oxygen species production in endothelial cells by facilitating Nox2 NADPH oxidase complex formation.

Recent evidence suggests that ClC-3, a member of the ClC family of Cl channels or Cl/H antiporters, plays a critical role in NADPH oxidase-derived reactive oxygen species (ROS) generation. However, the underling mechanisms remain unclear. In this study we investigated the effects and mechanisms of ClC-3 on NADPH oxidase activation and ROS generation in endothelial cells.

Transmembrane member 16A participates in hydrogen peroxide-induced apoptosis by facilitating mitochondria-dependent pathway in vascular smooth muscle cells.

Background And Purpose: Transmembrane member 16A (TMEM16A), an intrinsic constituent of the Ca -activated Cl channel, is involved in vascular smooth muscle cell (VSMC) proliferation and hypertension-induced cerebrovascular remodelling. However, the functional significance of TMEM16A for apoptosis in basilar artery smooth muscle cells (BASMCs) remains elusive. Here, we investigated whether and how TMEM16A contributes to apoptosis in BASMCs.

Ca/Calmodulin-Dependent Protein Kinase II γ-Dependent Serine727 Phosphorylation Is Required for TMEM16A Ca-Activated Cl Channel Regulation in Cerebrovascular Cells.

Background: TMEM16A is a critical component of Ca-activated chloride channels (CaCCs) and mediates basilar arterial smooth muscle cell (BASMC) proliferation in hypertensive cerebrovascular remodeling. CaMKII is a negative regulator of CaCC, and four CaMKII isoforms (α, β, γ and δ) are expressed in vasculature; however, it is unknown which and how CaMKII isoforms affect TMEM16A-associated CaCC and BASMC proliferation.

Methods and results: Patch clamp and small interfering RNA (siRNA) knockdown of different CaMKII isoforms revealed that only CaMKIIγ inhibited native Ca-activated chloride currents (I) in BASMCs.

WNK1 is required for proliferation induced by hypotonic challenge in rat vascular smooth muscle cells.

Hypotonic challenge evoked vascular cell proliferation through activation of volume-regulated Cl channel (VRCC), leading to a decrease in the intracellular Cl concentration ([Cl]). We hypothesize that the decrease in [Cl] may activate one or several Cl-sensitive kinases, resulting in a subsequent signaling cascade. In this study we demonstrated that WNK1, a Cl-sensitive kinase, was involved in VRCC-induced proliferative signaling pathway in A10 vascular smooth muscle cells in vitro.

Xyloketal B alleviates cerebral infarction and neurologic deficits in a mouse stroke model by suppressing the ROS/TLR4/NF-κB inflammatory signaling pathway.

Xyloketal B (Xyl-B) is a novel marine compound isolated from mangrove fungus Xylaria sp. We previously demonstrated that pretreatment with Xyl-B exerted neuroprotective effects and attenuated hypoxic-ischemic brain injury in neonatal mice. In the present study we investigated the neuroprotective effects of pre- and post-treatment with Xyl-B in adult mice using a transient middle cerebral artery occlusion (tMCAO) model, and explored the underlying mechanisms.

TMEM16A Contributes to Endothelial Dysfunction by Facilitating Nox2 NADPH Oxidase-Derived Reactive Oxygen Species Generation in Hypertension.

Ca-activated Cl channels play a crucial role in various physiological processes. However, the role of TMEM16A in vascular endothelial dysfunction during hypertension is unclear. In this study, we investigated the specific involvement of TMEM16A in regulating endothelial function and blood pressure and the underlying mechanism.

Endophilin A2 Influences Volume-Regulated Chloride Current by Mediating ClC-3 Trafficking in Vascular Smooth Muscle Cells.

Background: Previous research has demonstrated that ClC-3 is responsible for volume-regulated Clcurrent (I) in vascular smooth muscle cells (VSMCs). However, it is still not clear whether and how ClC-3 is transported to cell membranes, resulting in alteration ofI.Methods and Results:Volume-regulated chloride current (I) was recorded by whole-cell patch clamp recording, and Western blotting and co-immunoprecipitation were performed to examine protein expression and protein-protein interaction.

Endophilin-A2-mediated increase in scavenger receptor expression contributes to macrophage-derived foam cell formation.

Background And Aims: Macrophage-derived foam cell formation (MFCF) is a crucial step in the pathogenesis of atherosclerosis. Uptake of oxidized low-density lipoprotein (oxLDL) by scavenger receptors is indispensable for MFCF. Endophilin-A2 has been reported to regulate clathrin-mediated endocytosis (CME).

Endophilin A2 protects H2O2-induced apoptosis by blockade of Bax translocation in rat basilar artery smooth muscle cells.

Background: Apoptosis plays a central role in maintaining the normal cell number and tissue homeostasis. Endophilins are a family of evolutionarily conserved proteins that have the critical role in endocytosis. Here, we determined whether endophilin A2 (EndoII) contributes to hydrogen peroxide (H2O2)-induced apoptosis in rat basilar artery smooth muscle cells (BASMCs) and the underlying mechanisms.

Suppression of Kv1.5 protects against endothelial apoptosis induced by palmitate and in type 2 diabetes mice.

Aims: Palmitate, a common saturated free fatty acid, induces endothelial apoptosis in vitro in culture endothelial cells and in vivo in type 2 diabetes mellitus (T2DM) patients. The present study aimed to investigate whether Kv1.5 regulates palmitate-induced endothelial apoptosis and endothelial dysfunction in T2DM.

TRPC3 channel confers cerebrovascular remodelling during hypertension via transactivation of EGF receptor signalling.

Aims: Ionic perturbation in vascular smooth muscle cells contributes to cerebrovascular remodelling in the setting of hypertension, but the role of transient receptor potential (TRP) channel superfamily remains unknown. The present study was conducted to define the contribution of TRP channels to cerebrovascular remodelling.

Methods And Results: By integrating quantitative PCR, western blotting, patch clamping, and Ca(2+) imaging, we identified TRP channel, subfamily canonical, member 3 (TRPC3) as the channel subtype most considerably elevated in basilar arteries of two-kidney, two-clip stroke-prone hypertensive rats.