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Abstract：
De-differentiation and subsequent increased proliferation and inflammation of vascular smooth muscle cells (VSMCs) is one of the mechanisms of atherogenesis. Maintaining VSMCs in a contractile differentiated state is therefore a promising therapeutic strategy for atherosclerosis. We have reported the 18-base myogenetic oligodeoxynucleotide, iSN04, which serves as an anti-nucleolin aptamer and promotes skeletal and myocardial differentiation. The present study investigated the effect of iSN04 on VSMCs because nucleolin has been reported to contribute to VSMC de-differentiation under pathophysiological conditions. Nucleolin is localized in the nucleoplasm and nucleoli of both rat and human VSMCs. iSN04 without a carrier was spontaneously incorporated into VSMCs, indicating that iSN04 would serve as an anti-nucleolin aptamer. iSN04 treatment decreased the ratio of 5-ethynyl-2\'-deoxyuridine (EdU)-positive proliferating VSMCs and increased the expression of α-smooth muscle actin, a contractile marker of VSMCs. iSN04 also suppressed angiogenesis of mouse aortic rings ex vivo, which is a model of pathological angiogenesis involved in plaque formation, growth, and rupture. These results demonstrate that antagonizing nucleolin with iSN04 preserves VSMC differentiation, providing a nucleic acid drug candidate for the treatment of vascular disease.
摘要：
血管平滑肌细胞（VSMC）的去分化和随后的增殖和炎症增加是动脉粥样硬化形成的机制之一。因此,将VSMC维持在收缩分化状态是动脉粥样硬化的有希望的治疗策略。我们已经报道了18个碱基的成肌寡脱氧核苷酸，iSN04,其充当抗核仁素适体并促进骨骼和心肌分化。本研究调查了iSN04对VSMC的影响，因为据报道，核仁素在病理生理条件下有助于VSMC去分化。核仁素位于大鼠和人VSMC的核质和核仁中。没有载体的iSN04自发地掺入到VSMC中，表明iSN04将充当抗核仁素适体。iSN04治疗降低了5-乙炔基-2'-脱氧尿苷（EdU）阳性增殖VSMC的比例，并增加了α-平滑肌肌动蛋白的表达，VSMC的收缩标记。iSN04还抑制了离体小鼠主动脉环的血管生成，这是一个与斑块形成有关的病理性血管生成模型，增长,和破裂。这些结果表明，用iSN04拮抗核仁素可以保留VSMC分化，提供用于治疗血管疾病的核酸候选药物。
