Abstract
The Akt plays an important role in regulating cardiac growth, myocardial angiogenesis, and cell death in cardiac myocytes. However, there are few studies to focus on the responses of the Akt pathway to cardiac contractility modulation (CCM) in a chronic heart failure (HF) model. In this study, the effects of CCM on the treatment of HF in a rabbit model were investigated. Thirty six-month-old rabbits were randomly separated into control, HF, and CCM groups. The rabbits in HF and CCM groups were pressure uploaded, which can cause an aortic constriction. Then, CCM was gradually injected to the myocardium of rabbits in the CCM group, and this process lasted for four weeks with six hours per day. Rabbit body weight, heart weight, and heart beating rates were recorded during the experiment. To assess the CCM impacts, rabbit myocardial histology was examined as well. Additionally, western blot analysis was employed to measure the protein levels of Akt, FOXO3, Beclin, Pi3k, mTOR, GSK-3β, and TORC2 in the myocardial histology of rabbits. Results showed that the body and heart weight of rabbits decreased significantly after suffering HF when compared with those in the control group. However, they gradually recovered after CCM application. The CCM significantly decreased collagen volume fraction in myocardial histology of HF rabbits, indicating that CCM therapy attenuated myocardial fibrosis and collagen deposition. The levels of Akt, FOXO3, Beclin, mTOR, GSK-3β, and TORC2 were significantly downregulated, but Pi3k concentration was greatly upregulated after CCM utilization. Based on these findings, it was concluded that CCM could elicit positive effects on HF therapy, which was potentially due to the variation in the Pi3k/Akt signaling pathway.
Highlights
Chronic heart failure (CHF) is the terminal stage of various structural and functional cardiac diseases [1]. is disease can cause a progressive reduction in cardiac output since it depresses the cardiac contractility and influences the conduction pathways as well by causing a delay in the onset of right or left ventricular systole [2,3]
Experimental Design and Management. e rabbits were randomly separated into three groups, namely, control, HF, and contractility modulation (CCM) groups, and each group contained 10 rabbits. e rabbits in the control group only received thoracotomy. e HF is characterized by the transition from an initial compensatory response to decompensation, which can be partially mimicked by transverse aortic constriction in rodent models [15]. erefore, in the HF group, rabbits were treated by thoracotomy and ascending aortic cerclage. e rabbits in the CCM group suffered from thoracotomy, ascending aortic cerclage, and CCM application with a period of 4 weeks after HF occurred
At the end of this experiment, 27 rabbits survived (i.e., 9 rabbits in each experimental group), which met the criteria of HF. eir weight, including body and heart weight, significantly decreased for HF rabbits when compared with those in the control group and they progressively increased after CCM application (Table 1). e CCM signals significantly decreased the heart rate of HF rabbits, and similar heart beat rates were observed between rabbits in control and CCM groups (Table 1)
Summary
Chronic heart failure (CHF) is the terminal stage of various structural and functional cardiac diseases [1]. is disease can cause a progressive reduction in cardiac output since it depresses the cardiac contractility and influences the conduction pathways as well by causing a delay in the onset of right or left ventricular systole [2,3]. E Akt is the effector of Pi3k and is essential during postnatal cardiac development that is achieved predominantly by hypertrophy rather than hyperplasia of individual cardiomyocytes [9]. It suggested that increasing Akt expression in cells could promote their hypertrophy and hyperplasia. Cardiac contractility modulation (CCM) is a series of nonexcitatory signals which can be applied during the absolute refractory period to enhance the strength of left ventricular contraction without increasing myocardial oxygen consumption [11,12]. E process of contraction force increasing is mediated by reversing the molecular remodeling and restoring the expression of several calcium-handling proteins in myocardial hypertrophy with heart failure (HF) [13]. It was reported that CCM could significantly alter the cytoskeleton proteins and matrix metalloproteinases [14]. e Pi3k/Akt signaling pathway was activated by a serious of internal- and external-cellular proteins via the phosphorylation at r 308 and Ser 473 [8]
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