TAT-Gap19 TFA

TAT-Gap19 TFA is a Cx mimetic peptide and a specific inhibitor of connexin 43 (Cx43) hemichannels (HCs)^[1-2]. TAT-Gap19 TFA blocks Cx43 hemichannel activity by inhibiting glutamate-induced ATP release, and can cross the blood-brain barrier to reduce cerebral infarct volume and alleviate liver fibrosis. TAT-Gap19 TFA can be used for research related to cerebral ischemia-reperfusion injury and liver fibrosis^[3-4].

In vitro, TAT-Gap19 TFA (400µM) treatment of gingival fibroblasts for 24 hours. TAT-Gap19 TFA significantly upregulated the expression of genes including various MMPs, TGF-β signaling molecules, Tenascin-C, and VEGF-A, while significantly downregulating the expression of pro-fibrotic molecules including various extracellular matrix proteins, myofibroblast, and cell contractility-related molecules^[5]. Human coronary artery endothelial cells (TICAE) and human microvascular endothelial cells (TIME) were pretreated with TAT-Gap19 TFA (100µM) for 30 minutes, followed by X-ray irradiation (0.1 and 5Gy). TAT-Gap19 TFA significantly reduced radiation-induced intracellular reactive oxygen species (ROS) production, cell death, the expression of pro-inflammatory factors/adhesion molecules, and premature cellular senescence, thereby alleviating radiation-induced endothelial cell damage^[6].

In vivo, Balb/c mice with liver fibrosis induced by eight weeks of thioacetamide (TAA) administration were treated with TAT-Gap19 TFA (1mg/kg/day) via an osmotic pump implanted in the peritoneal cavity for two weeks. TAT-Gap19 TFA significantly reduced hepatic collagen deposition and the number of activated hepatic stellate cells (α-SMA-positive cells), increased superoxide dismutase (SOD) activity, and decreased lymphotactin production^[7]. C57BL/6 mice with non-alcoholic steatohepatitis (NASH) were treated with TAT-Gap19 TFA (1mg/kg/day, delivered continuously via an implanted osmotic pump for two weeks). TAT-Gap19 TFA significantly reduced liver steatosis score, lobular inflammation score, NAFLD activity score (NAS), hepatic triglyceride and cholesterol levels, and levels of the pro-inflammatory cytokines IL-1β and TNF-α, while increasing SOD activity^[8].

References:
[1] Abudara V, Bechberger J, Freitas-Andrade M, et al. The connexin43 mimetic peptide Gap19 inhibits hemichannels without altering gap junctional communication in astrocytes. Front Cell Neurosci. 2014 Oct 21;8:306.
[2] Crespo Yanguas S, da Silva TC, Pereira IVA, et al. TAT-Gap19 and Carbenoxolone Alleviate Liver Fibrosis in Mice. Int J Mol Sci. 2018 Mar 12;19(3):817.
[3] Walrave L, Pierre A, Albertini G, et al. Inhibition of astroglial connexin43 hemichannels with TAT-Gap19 exerts anticonvulsant effects in rodents. Glia. 2018 Aug;66(8):1788-1804.
[4] Quan M, Lv H, Liu Z, et al. MST1 Suppresses Disturbed Flow Induced Atherosclerosis. Circ Res. 2022 Oct 14;131(9):748-764.
[5] Tarzemany R, Jiang G, Jiang JX, et al. Connexin 43 Hemichannels Regulate the Expression of Wound Healing-Associated Genes in Human Gingival Fibroblasts. Sci Rep. 2017 Oct 26;7(1):14157.
[6] Ramadan R, Vromans E, Anang DC, et al. Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage. Front Pharmacol. 2020 Mar 5;11:212.
[7] Crespo Yanguas S, da Silva TC, et al. TAT-Gap19 and Carbenoxolone Alleviate Liver Fibrosis in Mice. Int J Mol Sci. 2018 Mar 12;19(3):817.
[8] Willebrords J, Cogliati B, Pereira IVA, et al. Inhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in mice. Sci Rep. 2017 Aug 15;7(1):8268.

TAT-Gap19 TFA是一种Cx模拟肽，是一种特定的连接蛋白43（Cx43）半通道（HC）抑制剂^[1-2]。TAT-Gap19 TFA可抑制谷氨酸诱导的ATP释放来阻断Cx43半通道活性，同时通过透过血脑屏障以减少脑梗死体积和减轻肝纤维化。TAT-Gap19 TFA可用于脑缺血再灌注损伤和肝纤维化的相关研究^[3-4]。

在体外，TAT-Gap19 TFA（400μM）处理牙龈成纤维细胞24小时，显著上调了包括多种MMPs、TGF-β信号分子、Tenascin-C和VEGF-A在内的基因表达，同时显著下调了包括多种细胞外基质蛋白、肌成纤维及细胞收缩性相关分子在内的促纤维化分子表达^[5]。TAT-Gap19 TFA（100μM）预处理人冠状动脉内皮细胞（TICAE）及人微血管内皮细胞（TIME）30分钟，随后以X射线（0.1和5Gy）照射。TAT-Gap19 TFA显著减少了辐射诱导的细胞内活性氧（ROS）产生、细胞死亡、促炎因子/黏附分子的表达以及早衰性细胞衰老，从而减轻了辐射诱导的内皮细胞损伤^[6]。

在体内，TAT-Gap19 TFA（1mg/kg/day）通过植入腹腔的渗透泵持续给药两周，用于处理经硫代乙酰胺（TAA）诱导肝纤维化八周后的Balb/c小鼠。TAT-Gap19 TFA显著降低了肝脏的胶原沉积和活化的肝星状细胞（α-SMA阳性细胞）数量，同时增加了超氧化物歧化酶（SOD）的活性并降低了淋巴趋化素的产生^[7]。TAT-Gap19 TFA（1mg/kg/day，通过植入腹腔的渗透泵持续给药两周）用于处理非酒精性脂肪性肝炎（NASH）的C57BL/6小鼠。TAT-Gap19 TFA显著降低了肝脏脂肪变性评分、小叶炎症评分、非酒精性脂肪肝病活动度评分（NAS）、肝脏甘油三酯和胆固醇水平，以及促炎细胞因子IL-1β和TNF-α的水平，同时增加了SOD的活性^[8]。