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.