在心室卸载后“逆向心脏重构”期间，视网膜母细胞瘤蛋白/E2F-1 通路的可逆调节。
Reversible regulation of the retinoblastoma protein/E2F-1 pathway during "reverse cardiac remodelling" after ventricular unloading.
机构信息
Department of Pathology and Neuropathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
出版信息
J Heart Lung Transplant. 2010 Jan;29(1):117-24. doi: 10.1016/j.healun.2009.09.017.
BACKGROUND
Cyclin D1, the retinoblastoma (Rb) protein, and the E2F transcription factors are involved in the pathogenesis of cardiac hypertrophy. Cyclin D1/cdk4 complexes, by phosphorylation, inactivate Rb, thereby abrogating its growth-inhibitory effect. Ventricular unloading is associated with reversible regulation of numerous cardiomyocyte molecular systems and decreased hypertrophy. Accordingly, the hypothesis whether the Rb/E2F-1 pathway is altered by ventricular unloading was tested, and correlations with the cyclin D1 protein expression and cardiomyocyte diameters were explored.
METHODS
In 21 paired myocardial samples (before and after unloading) from patients with congestive heart failure (CHF), cyclin D1, phosphorylated Rb (pRb), its homologues p107 and p130 (pocket proteins), and E2F-1 were immunohistochemically investigated and morphometrically quantified. Cardiomyocyte diameters were morphometrically determined.
RESULTS
Cyclin D1 and the proteins of the Rb/E2F-1 pathway were significantly increased during CHF compared with controls and were significantly decreased after unloading. Cyclin D1, pRb, and p130 protein expression correlated significantly with cardiomyocyte diameters. A significant positive correlation was noted between the pocket proteins, E2F-1, and cyclin D1.
CONCLUSION
Increased protein expression of phosphorylated (inactivated) Rb and the pocket proteins is associated with cardiomyocyte hypertrophy in CHF. Rb inactivation might be explained by phosphorylation by increased numbers of cyclin D1/cdk4 complexes associated with cardiomyocyte hypertrophy. However, ventricular unloading can reversibly regulate this process. These data underscore the importance of cell cycle regulatory proteins in the pathogenesis of CHF-associated (maladaptive) cardiomyocyte hypertrophy and might offer novel clues for pharmacologic approaches of congestive heart failure.
背景
细胞周期蛋白 D1、视网膜母细胞瘤蛋白（Rb）和 E2F 转录因子参与了心肌肥厚的发病机制。细胞周期蛋白 D1/cdk4 复合物通过磷酸化使 Rb 失活，从而消除其生长抑制作用。心室卸载与许多心肌细胞分子系统的可逆调节和心肌肥厚减少有关。因此，检测了 Rb/E2F-1 通路是否因心室卸载而改变，并探讨了与细胞周期蛋白 D1 蛋白表达和心肌细胞直径的相关性。
方法
在 21 对充血性心力衰竭（CHF）患者的心肌样本（卸载前后）中，用免疫组织化学方法检测细胞周期蛋白 D1、磷酸化 Rb（pRb）、其同源物 p107 和 p130（口袋蛋白）和 E2F-1，并进行形态计量学定量。心肌细胞直径用形态计量学方法确定。
结果
与对照组相比，CHF 期间细胞周期蛋白 D1 和 Rb/E2F-1 通路的蛋白表达显著增加，卸载后显著降低。细胞周期蛋白 D1、pRb 和 p130 蛋白表达与心肌细胞直径显著相关。口袋蛋白、E2F-1 和细胞周期蛋白 D1 之间存在显著的正相关。
结论
在 CHF 中，磷酸化（失活）Rb 和口袋蛋白的蛋白表达增加与心肌细胞肥大有关。Rb 失活可能是由于与心肌细胞肥大相关的细胞周期蛋白 D1/cdk4 复合物数量增加而导致的磷酸化。然而，心室卸载可以可逆地调节这个过程。这些数据强调了细胞周期调节蛋白在 CHF 相关（适应性不良）心肌细胞肥大发病机制中的重要性，并可能为充血性心力衰竭的药物治疗提供新的线索。
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