Donker Dirk W, Maessen Jos G, Verheyen Fons, Ramaekers Frans C, Spätjens Roel L H M G, Kuijpers Helma, Ramakers Christian, Schiffers Paul M H, Vos Marc A, Crijns Harry J G M, Volders Paul G A
Department of Cardiology, Cardiovascular Research Institute Maastricht, Academic Hospital Maastricht, 6202 AZ Maastricht, The Netherlands.
Am J Physiol Heart Circ Physiol. 2007 May;292(5):H2324-32. doi: 10.1152/ajpheart.00392.2006. Epub 2007 Jan 12.
It is poorly understood how mechanical stimuli influence in vivo myocardial remodeling during chronic hemodynamic overload. Combined quantitation of ventricular mechanics and expression of key proteins involved in mechanotransduction can improve fundamental understanding. Adult anesthetized dogs (n = 20) were studied at sinus rhythm (SR) and 0, 3, 10, and 35 days of complete atrioventricular block (AVB). Serial left ventricular (LV) myofiber mechanics were measured. Repeated LV biopsies were analyzed for mRNA and/or protein expression of beta(1D)-integrin, melusin, Akt, GSK3beta, muscle LIM protein (MLP), four-and-a-half LIM protein 2 (fhl2), desmin, and calpain. Upon AVB, increased ejection strain (0.29 +/- 0.01 vs. 0.13 +/- 0.02, SR) and end-diastolic stress (4.8 +/- 1.1 vs. 2.7 +/- 0.4 kPa) dominated mechanical changes. Brain natriuretic peptide plasma levels were correspondingly high (33 +/- 4 vs. 19 +/- 1 pg/ml, SR). beta(1D)-Integrin protein expression increased chronically after AVB. Melusin was temporarily overexpressed (+33 +/- 9%, 3 days AVB vs. SR), followed by elevated ratios of phosphorylated (P)-Akt to Akt and P-GSK3beta to GSK3beta (+26 +/- 6% and +30 +/- 8% at 10 days AVB vs. SR). These changes corresponded to peak hypertrophic growth at 3 to 10 days. MLP increased gradually to maxima at chronic AVB (+36 +/- 7%). In contrast, fhl2 (-22 +/- 3%, 3 days) and desmin (-30 +/- 9%, 10 days AVB) transiently declined but recovered at chronic AVB. Calpain protein expression remained unaltered. In conclusion, volume overload after AVB causes a transient compromise of cytoskeletal integrity based, at least partly, on transcriptional downregulation. Subsequent cytoskeletal reorganization coincides with the upregulation of melusin, P-Akt, P-GSK3beta, and MLP, indicating a strong drive to compensated hypertrophy.
目前对于慢性血流动力学过载期间机械刺激如何影响体内心肌重塑的了解还很有限。结合心室力学定量和机械转导相关关键蛋白的表达分析，有助于加深对这一过程的基本认识。本研究选取了20只成年麻醉犬，在窦性心律（SR）以及完全性房室传导阻滞（AVB）后的0、3、10和35天进行观察。连续测量左心室（LV）肌纤维力学参数，并多次进行LV活检，分析β(1D)-整合素、melusin、Akt、GSK3β、肌肉LIM蛋白（MLP）、四半LIM蛋白2（fhl2）、结蛋白和钙蛋白酶的mRNA和/或蛋白表达。AVB发生后，射血应变增加（SR组为0.13±0.02，AVB组为0.29±0.01）以及舒张末期应力增加（SR组为2.7±0.4kPa，AVB组为4.8±1.1kPa）成为主要的力学变化。血浆脑钠肽水平相应升高（SR组为19±1pg/ml，AVB组为33±4pg/ml）。AVB后β(1D)-整合素蛋白表达长期增加。Melusin在短期内过度表达（AVB 3天组较SR组增加33±9%），随后磷酸化（P）-Akt与Akt以及P-GSK3β与GSK3β的比值升高（AVB 10天组较SR组分别增加26±6%和30±8%）。这些变化与3至10天的肥厚生长高峰相对应。MLP在慢性AVB时逐渐增加至最大值（增加36±7%）。相反，fhl2（AVB 3天组下降22±3%）和结蛋白（AVB 10天组下降30±9%）短暂下降，但在慢性AVB时恢复。钙蛋白酶蛋白表达保持不变。总之，AVB后的容量过载至少部分基于转录下调导致细胞骨架完整性的短暂受损。随后的细胞骨架重组与melusin、P-Akt、P-GSK3β和MLP的上调同时发生，表明存在强烈的代偿性肥大驱动机制。
