Significance of interaction between myocytes and non-myocytes in ventricular hypertrophy.

越来越多的证据表明，心肌细胞(MC)和非心肌细胞(NMC)的相互作用发生在心肌肥厚的重塑过程中。我们建立了单纯的MC培养和MC-NMC共培养体系，以检测内皮素-1(ET-1)、心肌营养素-1(CT-I)和细胞外基质蛋白(Fin)的相互作用。ET-1和CT-I主要在NMC表达，MC表达较少。NMC培养上清液中也检测到大量ET-L和CT-I。当MCs与NMC共同培养时，MCs诱导肥大反应，如ANP/BNP的产生，细胞尺寸的增加和蛋白质合成的增加。ETA受体拮抗剂或抗CT-1抗体显著抑制共培养的肥大反应，BQ1-23和抗CT-I抗体的作用是相加的。这些结果清楚地表明ET-1和CT-I是主要由NMC分泌的旁分泌肥大因子。我们还观察了Fn对MC的影响，Fn包衣呈剂量依赖性地促进蛋白质合成和ANP/BNP的分泌，并伴随着FAK的磷酸化。RGD抑制FIN诱导的MC肥大反应和共培养的肥大反应，提示FN不仅是MC肥大的被动参与者，而且是MC肥大的主动分子。本研究表明MC-NMC相互作用通过旁分泌因子和细胞外基质蛋白在心室重构中发挥重要作用。

Growing evidence indicates that the interaction of myocyte (MC) and non-MC .(NMC) occurs in the remodeling of ventricular hypertrophy. We have developed the pure MC culture and MC-NMC co-culture system to examine the involvement of endothelin-1 (ET-1), cardiotrophin-1 (CT-i) and extracellular matrix proteins, fibronectin (Fin) in the interaction.ET-1 and CT-i mRNA were expressed mainly in NMC and much less expressed in MC.The substantial amount of ET-l and CT-i were also detected in the culture medium of the NMC culture. When MCs were co-cultured with NMC, MCs induce hypertrophic responses, such as ANP/BNP production, the increase in cell size and augmentation of protein synthesis. ETA receptor antagonist or anti-CT-1 antibody significantly suppressed the hypertrophic response in the co-culture, and the effect of BQ1 23 and anti CT-i Ab was additive in nature. These findings clearly indicate that ET-1 and CT-i are paracrine hypertrophic factors mainly secreted from NMC.We also examined the effect of Fn on MC.Fn-coating dose-dependently increased protein synthesis and ANP/BNP secretion, accompanied by FAK phosphorylation. The RGD peptide suppressed the Fin-induced hypertrophied response of MC on the pure MC and the hypertrophic response observed in the co-culture, suggesting that Fn is not merely passive participant but an active molecute in the MC hypertrophy. The present study indicates important roles of the MC-NMC interaction in the ventricular remodeling via paracrine factors and extracellular matrix proteins.