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 Ca2+ 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 Ca2+ 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.
