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  • br The role of chemokine and AD Chemokines are


    The role of chemokine and AD Chemokines are small cytokine proteins that are involved in various immunological and physiological functions. These proteins can be involved in cell migration and localization during homeostasis and inflammation, and as such, they were named chemokines [80]. Chemokines can be classified into five types, according to the arrangement of n-terminal cysteine residues, namely, CXC, CC, CX3C, XC and CX [81]. Of these five classes, only the CX superfamily members have been found in zebrafish [82]. More than 50 chemokines have been discovered, most of them belonging to the CXC and CC super families, which are the main subfamilies in humans and mice. Besides the immune responses, chemokines also participate in other physiological processes like migration and organogenesis, inflammatory diseases, neurological development and angiogenesis [[83], [84], [85], [86]]. The CC superfamily has 28 members, Chemokine (CC motif) ligand (CCL) 1 to CCL28. There have been few studies in relation to the CC superfamily and AD. CCL2, also known as monocyte chemotactic protein 1 (MCP-1), was reported by Tieu BC et al. to increase MCP-1 expression in mice when fused with Ang II, and MCP-1 receptor knock out reduced the infraction of inflammatory Hydrochlorothiazide in the aortic wall and protected against AD induced by Ang II [87]. Plasma PCP-1 concentrations were also observed to be increased in human AD patients [88]. CCL3 has another name – macrophage inflammatory protein (MIP) – and plasma MIP-1β levels were increased in human Stanford A AD patients [51]. Other members were not reported to be involved in AD. The CXC superfamily has 17 members, from Chemokine (C-X-C motif) ligand (CXCL) 1 to CXCL17. CXCL1 was reportedly recruited and had higher expression in dissected aortas of Ang II-induced AD mice; CXCL1 promoted the infiltration and activation of neutrophils, up-regulated local IL-6 expression and resulted in aortic expansion and rupture [89]. In another study, where cyclic mechanical stretch was used in the internal environment to simulate dissection of the aorta, the increase in CXCL1 was mediated by the activation of the JNK and P38 signaling pathways [90]. For CXCL8, also named IL-8, a role in AD has been described in the section above. Bone marrow CXCL12 levels were reduced in Ang II-induced dissected aortas [89]. No study of other members has been reported for AD.
    The role of GFs and AD In an earlier study, Francke U et al. reported that mutation of Gly1127Ser, which was a gene of the fibrillin-1 area of EGF, produced a mild form of autosomal dominantly inherited weakness of elastic tissue and was a risk factor for aortic aneurysm and dissection [91]. Similar results were also reported in a later article [92]. In a study published in 1993, genetic screening for AD was performed on 7 affected families and 22 sporadic patients and the authors found that there was a mutation in the EGF genes [93]. In 29 CE patients and seven autopsy cases, PDGF-β was found to be coupled with MMPs [94]. In human AD patients, PDGF-β levels were observed to be higher in dissected aortas, and its increase was mediated by macrophages and could disrupt extracellular matrix homeostasis and increase the stiffness of the aorta wall, resulting in compromised aorta compliance and the occurrence of AD [95]. The TGF family includes TGF-α and the TGF- sub-family, while the TGF-β sub-family members include TGF-β1, TGF-β2, TGF-β3, activation (activins), statins (inhibins), mueller\'s curb mass (Mullerian inhibitor substance, MIS) and more than 20 bone morphogenetic proteins (ipads morpho-based proteins, BMPs) [96]. Milewicz DM et al. reported that both TGF-β receptor 1 and TGF-β receptor 2 were increased in dissected human aortas, results that suggested that TGF-β plays an important role in the progression of AD [97]. In a subsequent study on screening for aortic dissection genes, the results showed that MYH11 and ACTA2 mutations could enhance TGF-β signaling [98]. In a recent study, the authors also reported that the TGF-β1 signaling pathway was significantly increased in dissected human aortas [99]. Tellides G provided new and strong evidence of higher TGF-β1 in AD patients [100]. Increased activation of TGF-β1 signaling was observed in the Ang II-induced mouse AD model, and microRNA-21 treatment further activated the TGF-β1 pathway and exacerbated AD formation [101]. In patients with thoracic aortic-aneurysm and dissection, mutations in TGF-β2 were observed [102]. In another study, the authors reported that TGF-β2 mutation easily predisposed subjects to thoracic aortic disease, including Marfan syndrome and AD [103]. Similar to TGF-β1 and TGF-β2, TGF-β3 mutation was also reported to be closely related to the occurrence of Marfan syndrome in a single center sample study [104]. That conclusion was corroborated by a later multi-national center for research [105]. In patients with early AD, several genes belonging to the TGF-β pathway had been changed, including BMP2, BMP4 and BMPα receptor 1 [106]. The other members of the TGF family were not reported to be involved in AD.