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    • Another intriguing finding was that rs might

    2018-10-25

    Another intriguing finding was that rs12455792 might modulate the essential pathophysiological processes in TAAD-SMCs apoptosis, fibers accumulation and proteoglycans degradation, by fine tuning the SMAD4 expression. As we all known, the ciprofloxacin is composed of 3 layers: tunica intima, tunica media and tunica adventitia. The tensile strength and elasticity of the aorta mainly depend on the tunica media, which is formed of concentrically arranged elastic fibers and SMCs (Milewicz et al., 2008). In response to pulsatile blood flow, SMCs regulate blood flow and pulse pressure via contracting and secreting vascular regulatory factors (Milewicz et al., 2008). Loss of vascular SMCs is a key event in progression of TAAD. Our study showed that the numbers of SMCs in tissues from CC group was significantly higher than variant group. The status of SMCs loss was more graveness in the latter. While SMAD4 expression was lower in variant group as described in Fig. 2, we hypothesized that SMCs loss might be related to decreased SMAD4 expression, since it played a pivotal role in SMCs proliferation and blood vessel remodeling. After induction of angiotensin II for 24h, the percentage of both early and late-stage apoptotic cells were notably higher in siRNA-SMAD4 group. This suggested that SMAD4 was really important in maintenance of the SMCs number and normal physiological function of aorta. We also found that the elastic fibers and reticular fibers (brownish-black) were more disorganized and accumulated in tissues from patients with CT or TT genotype. This suggested that rs12455792 might be associated with fiber organization. Although there were no literatures about relationship between fibers accumulation and vascular disorders, we believed that the increase of components in connective tissues might destroy the structural and functional integrity of aortic wall, and reduce its reactive potency to changed blood pressure. SMAD4 might be involved in this process. These viewpoints needed more investigations to confirm. We further demonstrated that the proteoglycans (e.g. Versican, Decorin) in matrix degraded more seriously in aorta tissues from CT or TT groups. Proteoglycans interact with hyaluronan to form large aggregates. They can retain water and create reversible compressive layer to protect vascular from lesions of pressure waves and shearing force (LeBaron et al., 1992). Thus, proteoglycans may play a pivotal role in maintaining the structural and functional integrity of the vascular wall. The degradation of proteoglycans may be responsible for vascular diseases (Evanko et al., 1999; Kenagy et al., 2006). In TAAD tissues, we observed that the degradation of Versican and Decorin was related to rs12455792 genotypes. Moreover, western blot data showed a significantly increased degradation of Versican in SMAD4-silenced SMCs, but it was rescued after the addition of ADAMTS-4 inhibitor. Our findings suggested that SMAD4 low expression might promote Versican degradation via ADAMTS-4. Versican was reported as main proteoglycan substrate of ADAMTS proteinases in the aorta (Sandy et al., 2001). With Movat\'s pentachrome (Fig. 4), we found that proteoglycans aggregates (aggregates without degradation were stained as bright-blue) were more in CC group than that in CT or TT group. This was consistent with the degradation status of relative groups which were reflected by western blot. There were several limitations in the current study: (1) Since all the subjects were recruited from eastern Han Chinese population, the association between SMAD4 SNPs and risk of TAAD might not be generalized to other ethnic groups. (2) Large cohort, multi-center investigations should be performed to provide more potent statistical power. (3) TAAD is a complicated process. Inflammation and lymphocytes recruitment often accompany medial degeneration in the pathogenesis of TAAD (He et al., 2006). Activated T cells and macrophages may contribute to the apoptosis of SMCs and degradation of the matrix (He et al., 2006). Generous studies revealed that low SMAD4 expression might facilitate lymphocytes accumulation and infiltration (Huss et al., 2011; Inamoto et al., 2016; Sakata et al., 2017; Zhang et al., 2016). Therefore, the association between rs12455792 and inflammation or lymphocytes recruitment in the progression of TAAD is encouraging enough to warrant further investigations.