Analysis of fibrosis in control or pressure overloaded rat hearts after mechanical unloading by heterotopic heart transplantation
Analysis of fibrosis in control or pressure overloaded rat hearts after mechanical unloading by heterotopic heart transplantation
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DOI：
10.1038/s41598-019-42263-1
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发表时间：
2019-04
影响因子：
4.6
通讯作者：
A. Schaefer;Y. Schneeberger;S. Schulz;S. Krasemann;Tessa R Werner;A. Piasecki;Grit Höppner;Christian Müller;Karoline Morhenn;K. Lorenz;D. Wieczorek;A. Schwoerer;T. Eschenhagen;H. Ehmke;H. Reichenspurner;J. Stenzig;F. Cuello
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作者：
A. Schaefer;Y. Schneeberger;S. Schulz;S. Krasemann;Tessa R Werner;A. Piasecki;Grit Höppner;Christian Müller;Karoline Morhenn;K. Lorenz;D. Wieczorek;A. Schwoerer;T. Eschenhagen;H. Ehmke;H. Reichenspurner;J. Stenzig;F. Cuello
通过植入左心室辅助装置（LVAD）进行机械卸载（MU）已成为临床常规。这一过程已被证明可以逆转心脏病理性重塑，但其潜在的分子机制尚不完全清楚。到目前为止，大多数研究都是在非标准化的人类样本或MU健康动物心脏中进行的。我们的研究调查心脏重塑过程中假手术的健康大鼠心脏和心脏进行标准化的病理性压力超负荷的横向主动脉缩窄（TAC）之前MU异位心脏移植（hHTx/MU）。大鼠接受假手术或TAC手术。在通过hHTx/MU进行MU之前，通过超声心动图监测疾病进展。将TAC或TAC与hHTx/MU组合后的心脏取出并通过组织学、蛋白质免疫印迹和基因表达分析进行分析。TAC手术导致心脏肥大和心功能受损。TAC心脏显示心肌细胞直径显著增加和轻度纤维化。与hHTx/MU后的心脏相比，TAC后的肥大相关基因表达更高。虽然在所有经受hHTx/MU的心脏中心肌细胞直径回归到假手术对照的水平，但纤维化重构显著加剧。在hHTx/MU后，所有心脏中促纤维化和纤维化相关基因的转录显著增强。参与兴奋-收缩偶联的肌节蛋白在TAC后显示显著较低的磷酸化水平，并且在hHTx/MU后显著降低总蛋白水平。无论疾病状态如何，在所有接受hHTX/MU的心脏中观察到心肌纤维化、心肌细胞萎缩和肌节蛋白丢失的发展。这些结果可能有助于解释由于心肌恢复不足导致LVAD移除率低的临床经验。
Mechanical unloading (MU) by implantation of left ventricular assist devices (LVAD) has become clinical routine. This procedure has been shown to reverse cardiac pathological remodeling, with the underlying molecular mechanisms incompletely understood. Most studies thus far were performed in non-standardized human specimens or MU of healthy animal hearts. Our study investigates cardiac remodeling processes in sham-operated healthy rat hearts and in hearts subjected to standardized pathological pressure overload by transverse aortic constriction (TAC) prior to MU by heterotopic heart transplantation (hHTx/MU). Rats underwent sham or TAC surgery. Disease progression was monitored by echocardiography prior to MU by hHTx/MU. Hearts after TAC or TAC combined with hHTx/MU were removed and analyzed by histology, western immunoblot and gene expression analysis. TAC surgery resulted in cardiac hypertrophy and impaired cardiac function. TAC hearts revealed significantly increased cardiac myocyte diameter and mild fibrosis. Expression of hypertrophy associated genes after TAC was higher compared to hearts after hHTx/MU. While cardiac myocyte cell diameter regressed to the level of sham-operated controls in all hearts subjected to hHTx/MU, fibrotic remodeling was significantly exacerbated. Transcription of pro-fibrotic and apoptosis-related genes was markedly augmented in all hearts after hHTx/MU. Sarcomeric proteins involved in excitation-contraction coupling displayed significantly lower phosphorylation levels after TAC and significantly reduced total protein levels after hHTx/MU. Development of myocardial fibrosis, cardiac myocyte atrophy and loss of sarcomeric proteins was observed in all hearts that underwent hHTX/MU regardless of the disease state. These results may help to explain the clinical experience with low rates of LVAD removal due to lack of myocardial recovery.