Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary.
Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany.
ESC Heart Fail. 2022 Aug;9(4):2585-2600. doi: 10.1002/ehf2.13973. Epub 2022 May 18.
Volume overload (VO) induced hypertrophy is one of the hallmarks to the development of heart diseases. Understanding the compensatory mechanisms involved in this process might help preventing the disease progression.
Therefore, the present study used 2 months old Wistar rats, which underwent an aortocaval fistula to develop VO-induced hypertrophy. The animals were subdivided into four different groups, two sham operated animals served as age-matched controls and two groups with aortocaval fistula. Echocardiography was performed prior termination after 4- and 8-month. Functional and molecular changes of several sarcomeric proteins and their signalling pathways involved in the regulation and modulation of cardiomyocyte function were investigated.
The model was characterized with preserved ejection fraction in all groups and with elevated heart/body weight ratio, left/right ventricular and atrial weight at 4- and 8-month, which indicates VO-induced hypertrophy. In addition, 8-months groups showed increased left ventricular internal diameter during diastole, RV internal diameter, stroke volume and velocity-time index compared with their age-matched controls. These changes were accompanied by increased Ca sensitivity and titin-based cardiomyocyte stiffness in 8-month VO rats compared with other groups. The altered cardiomyocyte mechanics was associated with phosphorylation deficit of sarcomeric proteins cardiac troponin I, myosin binding protein C and titin, also accompanied with impaired signalling pathways involved in phosphorylation of these sarcomeric proteins in 8-month VO rats compared with age-matched control group. Impaired protein phosphorylation status and dysregulated signalling pathways were associated with significant alterations in the oxidative status of both kinases CaMKII and PKG explaining by this the elevated Ca sensitivity and titin-based cardiomyocyte stiffness and perhaps the development of hypertrophy.
Our findings showed VO-induced cardiomyocyte dysfunction via deranged phosphorylation of myofilament proteins and signalling pathways due to increased oxidative state of CaMKII and PKG and this might contribute to the development of hypertrophy.
容量超负荷（VO）诱导的心肌肥厚是心脏病发展的标志之一。了解这个过程中涉及的代偿机制可能有助于预防疾病的进展。
因此，本研究使用 2 个月大的 Wistar 大鼠，通过腹主动脉-腔静脉瘘（aortocaval fistula）发展 VO 诱导的心肌肥厚。将动物分为四组，两组假手术动物作为年龄匹配的对照组，两组腹主动脉-腔静脉瘘动物。在 4 个月和 8 个月后，在实验结束前进行超声心动图检查。研究了几种肌节蛋白的功能和分子变化及其信号通路，这些信号通路参与调节和调制心肌细胞功能。
该模型的特点是所有组的射血分数均保持不变，并且在 4 个月和 8 个月时，心脏/体重比、左/右心室和心房重量均升高，表明发生了 VO 诱导的心肌肥厚。此外，与年龄匹配的对照组相比，8 个月组的左心室舒张末期内径、右心室内径、每搏量和速度时间指数均增加。这些变化伴随着 8 个月 VO 大鼠心肌细胞 Ca 敏感性和肌联蛋白基心肌细胞硬度的增加，与其他组相比。改变的心肌细胞力学与肌节蛋白肌钙蛋白 I、肌球蛋白结合蛋白 C 和肌联蛋白的磷酸化缺陷有关，也伴随着与这些肌节蛋白磷酸化相关的信号通路受损，与 8 个月 VO 大鼠的年龄匹配对照组相比。磷酸化状态受损和信号通路失调与 CaMKII 和 PKG 激酶的氧化状态显著改变有关，这解释了 Ca 敏感性和肌联蛋白基心肌细胞硬度的增加，也许是心肌肥厚的发展。
我们的发现表明，VO 诱导的心肌细胞功能障碍是通过肌丝蛋白和信号通路的磷酸化异常引起的，这是由于 CaMKII 和 PKG 的氧化状态增加，这可能有助于心肌肥厚的发展。
