Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage

Abstract

Background: Emerging evidence indicates an excess risk of late occurring cardiovascular diseases, especially atherosclerosis, after thoracic cancer radiotherapy. Ionizing radiation (IR) induces cellular effects which may induce endothelial cell dysfunction, an early marker for atherosclerosis. In addition, intercellular communication through channels composed of transmembrane connexin proteins (Cxs), i.e. Gap junctions (direct cell-cell coupling) and hemichannels (paracrine release/uptake pathway) can modulate radiation-induced responses and therefore the atherosclerotic process. However, the role of endothelial hemichannel in IR-induced atherosclerosis has never been described before. Materials and Methods: Telomerase-immortalized human Coronary Artery/ Microvascular Endothelial cells (TICAE/TIME) were exposed to X-rays (0.1 and 5 Gy). Production of reactive oxygen species (ROS), DNA damage, cell death, inflammatory responses, and senescence were assessed with or without applying a Cx43 hemichannel blocker (TAT-Gap19). Results: We report here that IR induces an increase in oxidative stress, cell death, inflammatory responses (IL-8, IL-1β, VCAM-1, MCP-1, and Endothelin-1) and premature cellular senescence in TICAE and TIME cells. These effects are significantly reduced in the presence of the Cx43 hemichannel-targeting peptide TAT-Gap19. Conclusion: Our findings suggest that endothelial Cx43 hemichannels contribute to various IR-induced processes, such as ROS, cell death, inflammation, and senescence, resulting in an increase in endothelial cell damage, which could be protected by blocking these hemichannels. Thus, targeting Cx43 hemichannels may potentially exert radioprotective effects.

HDL Inhibited Atherosclerosis Induced by Radiation Injury

“…Although some studies suggested that moderate ultraviolet radiation can prevent cardiovascular disease [19]. Low dose of ionizing radiation will increase the risk of cardiovascular disease, mainly cause endothelial cell damage and participate in the process of atherosclerosis [20,21].HDL plays an anti atherosclerotic role by reducing the deposition of cholesterol in tissues, thus limiting the occurrence and development of atherosclerosis [22].Our clinic studies showed that radiation exposure was high risk factor during atherosclerosis prevalence, HDL superior to reduce this risk. Radiation can induce apoptosis through oxidative stress, during the cell experiment, MAECs apoptosis increased and HDL may protect [23].…”

HDL Inhibited Atherosclerosis Induced by Radiation Injury

“…Nonetheless, some studies have suggested that moderate ultraviolet radiation has the potential to prevent cardiovascular disease [19]. Notwithstanding ionizing radiation even in low doses will aggravate the risk of cardiovascular disease, primarily causing endothelial cell damage which leads to the process of atherosclerosis [20,21]. HDL reduces the deposition of cholesterol into tissues thereby playing an anti-atherosclerotic role by preventing the occurrence and development of atherosclerosis [22].…”

Connexins in Cancer: Jekyll or Hyde?

“…Nicotinamide adenine dinucleotide (NAD + ), which can be transferred through GJs and taken up/released by hemichannels, also stabilizes telomeres through its role as a cofactor for sirtuins [ 117 ]. Furthermore, specific inhibition of Cx43 hemichannels via the mimetic peptide TAT-Gap19, which inhibits hemichannel activity by binding to the intracellular tail, preventing interaction with the intracellular loop [ 118 , 119 ], decreased radiation-induced senescence [ 120 ]. However, an additional study observed no changes in senescence of glioma cells upon overexpression of Cx43 [ 121 ].…”

“…Even the bystander effect, which is often thought of as requiring a direct coupling between cells, can be mediated by soluble factors in conditioned media, potentially through release and uptake by hemichannels [ 248 ]. This effect was recently shown to be inhibited by the hemichannel function-specific Cx43 mimetic peptide Gap19, suggesting that this effect is in fact due to hemichannels [ 120 , 249 ]. Both DNA damage-inducing ROS [ 120 , 246 , 249 ] and the antioxidant glutathione [ 250 , 251 ] are also able to pass through hemichannels.…”

“…This effect was recently shown to be inhibited by the hemichannel function-specific Cx43 mimetic peptide Gap19, suggesting that this effect is in fact due to hemichannels [ 120 , 249 ]. Both DNA damage-inducing ROS [ 120 , 246 , 249 ] and the antioxidant glutathione [ 250 , 251 ] are also able to pass through hemichannels. NAD + , which can be released and taken up by hemichannels [ 252 ], also plays a role in genomic stability through the activity of sirtuin deacetylases [ 253 , 254 ].…”