Doi K, Ikeda T, Itoh H, Ueyama K, Hosoda K, Ogawa Y, Yamashita J, Chun T H, Inoue M, Masatsugu K, Sawada N, Fukunaga Y, Saito T, Sone M, Yamahara K, Kook H, Komeda M, Ueda M, Nakao K
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Arterioscler Thromb Vasc Biol. 2001 Jun;21(6):930-6. doi: 10.1161/01.atv.21.6.930.
We recently reported that C-type natriuretic peptide (CNP) occurs in vascular endothelial cells and acts as a vascular-type natriuretic peptide. In the present study, we stimulated the cGMP cascade in proliferating smooth muscle cells (SMCs), in which particulate guanylate cyclase-B, the specific receptor for CNP, is predominantly expressed, by use of an adenovirus encoding rat CNP cDNA (Ad.CNP). In the Ad.CNP-treated cultured SMCs, CNP caused the growth inhibition of SMCs at G(1) phase with an early increase of p21(CIP1/WAF1) expression and subsequent upregulation of p16(INK4a). The expression of smooth muscle myosin heavy chain-2, which is the molecular marker of highly differentiated SMCs, was reinduced in the Ad.CNP-treated SMCs. The Ad.CNP-treated SMCs also reexpressed particulate guanylate cyclase-A, which shows high affinity to atrial and brain natriuretic peptide and is exclusively expressed in well-differentiated SMCs. CNP, which was overexpressed in rabbit femoral arteries in vivo at the time of balloon injury, significantly suppressed neointimal formation. Furthermore, an enhancement of the expression of smooth muscle myosin heavy chain-2 occurred in the residual neointima. In addition, early regeneration of endothelial cells was observed in the Ad.CNP-infected group. Thus, stimulation of cGMP cascade in proliferating dedifferentiated SMCs can induce growth inhibition and redifferentiation of SMCs with accelerated reendothelialization.
我们最近报道，C型利钠肽（CNP）存在于血管内皮细胞中，并作为一种血管型利钠肽发挥作用。在本研究中，我们通过使用编码大鼠CNP cDNA的腺病毒（Ad.CNP）刺激增殖的平滑肌细胞（SMC）中的cGMP级联反应，其中颗粒型鸟苷酸环化酶-B（CNP的特异性受体）在该细胞中主要表达。在经Ad.CNP处理的培养SMC中，CNP在G1期导致SMC生长抑制，p21（CIP1/WAF1）表达早期增加，随后p16（INK4a）上调。平滑肌肌球蛋白重链-2（高度分化的SMC的分子标志物）的表达在经Ad.CNP处理的SMC中重新诱导。经Ad.CNP处理的SMC还重新表达颗粒型鸟苷酸环化酶-A，其对心房利钠肽和脑利钠肽具有高亲和力，且仅在分化良好的SMC中表达。在体内球囊损伤时兔股动脉中过表达的CNP显著抑制了新生内膜形成。此外，在残留的新生内膜中平滑肌肌球蛋白重链-2的表达增强。另外，在Ad.CNP感染组中观察到内皮细胞的早期再生。因此，刺激增殖的去分化SMC中的cGMP级联反应可诱导SMC生长抑制和再分化，并加速内皮再形成。
