Kohno M, Yokokawa K, Yasunari K, Kano H, Minami M, Ueda M, Yoshikawa J
First Department of Internal Medicine, Osaka City University Medical School, Japan.
Circ Res. 1997 Oct;81(4):585-90. doi: 10.1161/01.res.81.4.585.
The migration of medial smooth muscle cells (SMCs) into the intima is proposed to be an important process of intimal thickening in atherosclerotic lesions. The present study examined the possible effect of a novel endothelium-derived relaxing peptide, C-type natriuretic peptide (CNP), on oxidized low-density lipoprotein (LDL)-induced migration of cultured human coronary artery SMCs by the Boyden's chamber method. The effect of CNP was compared with that of atrial and brain natriuretic peptides (ANP and BNP, respectively). Oxidized LDL stimulates SMC migration in a concentration-dependent manner between 20 and 200 micrograms/mL. This stimulation was chemotactic in nature but was not chemokinetic. By contrast, native LDL was without significant activity. CNP-22 clearly inhibited SMC migration stimulated with 200 micrograms/mL oxidized LDL in a concentration-dependent manner between 10(-9) and 10(-6) mol/L. ANP-(1-28) and BNP-32 also inhibited oxidized LDL-induced SMC migration at concentrations of 10(-7) and 10(-6) mol/L, but these effects were weaker than the effect of CNP-22. Such inhibition by these natriuretic peptides was paralleled by an increase in the cellular level of cGMP. Oxidized LDL-induced migration was significantly inhibited by a stable analogue of cGMP, 8-bromo-cGMP, or an activator of the cytosolic guanylate cyclase, sodium nitroprusside. These natriuretic peptides did not suppress the cell adhesion either in the absence or presence of oxidized LDL. These data indicate that oxidized LDL stimulates migration of human coronary artery SMCs and that natriuretic peptides, especially CNP, inhibit this stimulated SMC migration, at least in part, through a cGMP-dependent process. Taken together with the finding that oxidized LDL is present in the intima, CNP may play a role as a local antimigration factor during the process of intimal thickening in hypercholesterolemia-induced coronary atherosclerosis.
内侧平滑肌细胞（SMC）向内膜迁移被认为是动脉粥样硬化病变内膜增厚的一个重要过程。本研究采用Boyden小室法，检测了一种新型内皮源性舒张肽C型利钠肽（CNP）对氧化型低密度脂蛋白（LDL）诱导的培养人冠状动脉SMC迁移的可能影响。将CNP的作用与心房利钠肽和脑利钠肽（分别为ANP和BNP）的作用进行了比较。氧化型LDL在20至200微克/毫升之间以浓度依赖的方式刺激SMC迁移。这种刺激本质上是趋化性的，但不是化学促动性的。相比之下，天然LDL没有显著活性。CNP-22在10^(-9)至10^(-6)摩尔/升之间以浓度依赖的方式明显抑制200微克/毫升氧化型LDL刺激的SMC迁移。ANP-(1-28)和BNP-32在10^(-7)和10^(-6)摩尔/升浓度时也抑制氧化型LDL诱导的SMC迁移，但这些作用比CNP-22的作用弱。这些利钠肽的这种抑制作用与细胞内cGMP水平的升高平行。氧化型LDL诱导的迁移被cGMP的稳定类似物8-溴-cGMP或胞质鸟苷酸环化酶激活剂硝普钠显著抑制。这些利钠肽在不存在或存在氧化型LDL的情况下均不抑制细胞黏附。这些数据表明，氧化型LDL刺激人冠状动脉SMC迁移，利钠肽尤其是CNP至少部分通过cGMP依赖的过程抑制这种刺激的SMC迁移。结合氧化型LDL存在于内膜的发现，CNP可能在高胆固醇血症诱导的冠状动脉粥样硬化内膜增厚过程中作为局部抗迁移因子发挥作用。
