Abstract
BackgroundIn our previous study, we established the novel concept of a non-neuronal cardiac cholinergic system–cardiomyocytes produce ACh in an autocrine and/or paracrine manner. Subsequently, we determined the biological significance of this system–it played a critical role in modulating mitochondrial oxygen consumption. However, its detailed mechanisms and clinical implications have not been fully investigated.AimWe investigated if this non-neuronal cardiac cholinergic system was upregulated by a modality other than drugs and if the activation of the system contributes to favorable outcomes.ResultsCholine acetyltransferase knockout (ChAT KO) cells with the lowest cellular ACh levels consumed more oxygen and had increased MTT activity and lower cellular ATP levels compared with the control cells. Cardiac ChAT KO cells with diminished connexin 43 expression formed poor cell–cell communication, evidenced by the blunted dye transfer. Similarly, the ChAT inhibitor hemicholinium-3 decreased ATP levels and increased MTT activity in cardiomyocytes. In the presence of a hypoxia mimetic, ChAT KO viability was reduced. Norepinephrine dose-dependently caused cardiac ChAT KO cell death associated with increased ROS production. In in vivo studies, protein expression of ChAT and the choline transporter CHT1 in the hindlimb were enhanced after ischemia-reperfusion compared with the contralateral non-treated limb. This local effect also remotely influenced the heart to upregulate ChAT and CHT1 expression as well as ACh and ATP levels in the heart compared with the baseline levels, and more intact cardiomyocytes were spared by this remote effect as evidenced by reduced infarction size. In contrast, the upregulated parameters were abrogated by hemicholinium-3.ConclusionThe non-neuronal cholinergic system plays a protective role in both myocardial cells and the entire heart by conserving ATP levels and inhibiting oxygen consumption. Activation of this non-neuronal cardiac cholinergic system by a physiotherapeutic modality may underlie cardioprotection through the remote effect of hindlimb ischemia-reperfusion.
Highlights
Our previous studies using animal models of heart failure [1,2,3,4,5,6] and angiogenesis [7] focused on whether manipulating the parasympathetic nervous system may offer a beneficial therapeutic modality against cardiovascular diseases
Choline acetyltransferase knockout (ChAT KO) cells with the lowest cellular ACh levels consumed more oxygen and had increased MTT activity and lower cellular ATP levels compared with the control cells
We found that vagal nerve stimulation [4,6] and the acetylcholinesterase inhibitor donepezil [8,9] activated an ischemia or hypoxiaresistant system independent of their heart rate reduction effects [1,4,10] and provided a promising outcome by slowing the progression of cardiac remodeling associated with chronic heart failure
Summary
Our previous studies using animal models of heart failure [1,2,3,4,5,6] and angiogenesis [7] focused on whether manipulating the parasympathetic nervous system may offer a beneficial therapeutic modality against cardiovascular diseases. This study clearly indicated that the non-neuronal cardiac cholinergic system protected cardiomyocytes from energy depletion when the cardiac energy demand was enhanced, e.g., increased oxygen consumption due to a pathologically elevated cardiac workload. This system would be expected to be a barrier against hypoxic or reactive oxygen species stress because locally synthesized ACh would sequentially activate and amplify this system in an autocrine and paracrine manner into the entire heart [11]. We established the novel concept of a non-neuronal cardiac cholinergic system– cardiomyocytes produce ACh in an autocrine and/or paracrine manner. Its detailed mechanisms and clinical implications have not been fully investigated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
