Scientific Reports
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2015
·Vol. 5
·期 1
·1-10
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IF 5.578
Zhang Yong,Qin Wei,Zhang Longyin,Wu Xianxian,Du Ning,Hu Yingying,Li Xiaoguang,Shen Nannan,Xiao Dan,Zhang Haiying,Li Zhange,Zhang Yue,Yang Huan,Gao Feng,Du Zhimin,Xu Chaoqian,Yang Baofeng
Atherosclerosis, a chronic inflammatory disease, is the major cause of life-threatening complications such as myocardial infarction and stroke. Endothelial apoptosis plays a vital role in the initiation and progression of atherosclerotic lesions. Although a subset of microRNAs (miRs) have been identified as critical regulators of atherosclerosis, studies on their participation in endothelial apoptosis in atherosclerosis have been limited. In our study, we found that miR-26a expression was substantially reduced in the aortic intima of ApoE −/− mice fed with a high-fat diet (HFD). Treatment of human aortic endothelial cells (HAECs) with oxidized low-density lipoprotein (ox-LDL) suppressed miR-26a expression. Forced expression of miR-26a inhibited endothelial apoptosis as evidenced by MTT assay and TUNEL staining results. Further analysis identified TRPC6 as a target of miR-26a and TRPC6 overexpression abolished the anti-apoptotic effect of miR-26a. Moreover, the cytosolic calcium and the mitochondrial apoptotic pathway were found to mediate the beneficial effects of miR-26a on endothelial apoptosis. Taken together, our study reveals a novel role of miR-26a in endothelial apoptosis and indicates a therapeutic potential of miR-26a for atherosclerosis associated with apoptotic cell death.
研究领域:
心血管疾病
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 23
·16756
·
IF 5.6
Mengyuan Wang,Xingfang Zhang,Juan Guo,Shangze Yang,Fang Yang,Xingjuan Chen
Acute lung injury (ALI) is characterized by endothelial barrier disruption and associated inflammatory responses, and transient receptor potential cation channel 6 (TRPC6)—mediated Ca2+influx is critical for endothelial hyperpermeability. In this study, we investigated the role of TRPC6 in LPS—induced ALI, analyzed gene expression inWTandTRPC6-/-lungs using RNA sequencing, and explored the effects of TRPC6 in the LPS—induced hyperpermeability in human umbilical vein endothelial cells (HUVECs) to elucidate the underlying mechanisms. Intratracheal instillation of LPS caused edema in the mouse lungs. Deletion of TRPC6 reduced LPS—induced lung edema and decreased cell infiltration. RNA sequencing analysis suggested that downregulated cell adhesion molecules inTRPC6-/-lungs may be responsible for their resistance to LPS—induced injury. In addition, downregulation of TRPC6 significantly alleviated the LPS—induced decrease in eNOS expression in lung tissue as well as in HUVECs. Moreover, inhibition of TRPC6 with the channel antagonist larixyl led to a decrease in LPS—induced hyperpermeability and ROS production in HUVECs, which could be reversed by blocking eNOS. Our findings suggest that inhibition of TRPC6 ameliorates LPS—induced ALI, which may be achieved by acting on the cell adhesion molecule signaling pathway and participating in the regulation of eNOS levels in endothelial cells.Keywords:acute lung injury;TRPC6;eNOS;endothelial cells
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高影响因子
BIOCHEMICAL PHARMACOLOGY
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2025
·
IF 5.6
Lei Zhou,Xueying Wang,Li Ren,Yufan Wang,Xiaofeng Liu,Kehan Wu,Yuanyuan Gao,Yang Sun,Xia Lin,Hongdong Hao,Xiao-qiang Li,Wei Cao
The transient receptor potential canonical 6 (TRPC6) channel represents a promising therapeutic target for chronic kidney diseases (CKDs) involving glomerular and tubular dysfunction; however, the development of highly specific inhibitors remains a challenge. A high-throughput screen of 150,000 structurally diverse compounds targeting the non-conserved C-terminal domain of TRPC6 identified promising candidates, which were validated using microscale thermophoresis and calcium imaging. Screening identified Z3571 as a top candidate targeting the non-conserved C-terminal domain of TRPC6, exhibiting strong binding affinity (K D = 1.62 μM) and potent inhibition (IC 50 = 31.07 nM) with > 100-fold selectivity over TRPC3 and TRPC7. Z3571 was evaluated in both an adriamycin-induced podocyte injury model and a transforming growth factor-β1-stimulated tubular fibrosis models. Its functional efficacy was assessed in mouse models of focal segmental glomerulosclerosis (FSGS) and renal fibrosis. Z3571 demonstrated significant therapeutic effects in both in vitro and in vivo models of FSGS and renal fibrosis. Pharmacokinetic properties were analyzed via high-performance liquid chromatography. Pharmacokinetic profiling revealed favorable oral bioavailability, metabolic stability, and preferential renal accumulation. On-target effects were confirmed using Trpc6 -knockout cells and mice, while binding-site-mutated cells established target specificity. Z3571 exhibited no activity in Trpc6 -knockout models, confirming TRPC6 as its essential target. Additionally, site-directed mutagenesis confirmed Lys821 and His831 as critical residues mediating the interaction between Z3571 and TRPC6. These findings establish Z3571 as a highly selective and orally bioavailable TRPC6 inhibitor with robust efficacy, positioning it as a promising targeted therapy for CKDs involving glomerular and tubular dysfunction.
研究领域:
肾脏病学
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分子药理学
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药物发现
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结构生物学
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转化医学
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高影响因子
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