Abstract
BackgroundWe previously established that the non-neuronal cardiac cholinergic system (NNCCS) is equipped with cardiomyocytes synthesizes acetylcholine (ACh), which is an indispensable endogenous system, sustaining cardiac homeostasis and regulating an inflammatory status, by transgenic mice overexpressing choline acetyltransferase (ChAT) gene in the heart. However, whole body biological significances of NNCCS remain to be fully elucidated.Methods and resultsTo consolidate the features, we developed heart-specific ChAT knockdown (ChATKD) mice using 3 ChAT-specific siRNAs. The mice developed cardiac dysfunction. Factors causing it included the downregulation of cardiac glucose metabolism along with decreased signal transduction of Akt/HIF-1alpha/GLUT4, leading to poor glucose utilization, impairment of glycolytic metabolites entering the tricarboxylic (TCA) cycle, the upregulation of reactive oxygen species (ROS) production with an attenuated scavenging potency, and the downregulated nitric oxide (NO) production via NOS1. ChATKD mice revealed a decreased vagus nerve activity, accelerated aggression, more accentuated blood basal corticosterone levels with depression-like phenotypes, several features of which were accompanied by cardiac dysfunction.ConclusionThe NNCCS plays a crucial role in cardiac homeostasis by regulating the glucose metabolism, ROS synthesis, NO levels, and the cardiac vagus nerve activity. Thus, the NNCCS is suggested a fundamentally crucial system of the heart.
Highlights
We previously reported that the heart possesses a critical system to support the fundamental cardiac functions using components equipped with a cardiomyocyte to synthesize acetylcholine (ACh)
ChAT knockdown (ChATKD) hearts show the heart‐specific transgene expression and the choline acetyltransferase (ChAT) mRNA expression downregulation Western blot analysis using anti-green fluorescent protein (GFP) antibodies revealed that the transgene was restrictively expressed in the heart (Fig. 1a) because the IRES sequence enabled the simultaneous EmGFP and siRNA gene expressions for the ChAT downregulation
The ChAT mRNA and protein levels were lower in the ChATKD heart than in the control heart, suggesting that ChATKD mice downregulated cardiac neuronal cardiac cholinergic system (NNCCS), and the cardiac ACh synthesis was lower in the ChATKD heart, but it was not completely deleted because cardiac ACh levels of ChATKD hearts were almost a half of control levels
Summary
We previously reported that the heart possesses a critical system to support the fundamental cardiac functions using components equipped with a cardiomyocyte to synthesize acetylcholine (ACh). We developed mice with heart-specific characteristic siRNAs overexpression, which recognized ChAT mRNA specific 3′-UTR elements (ChATKD). They showed several cardiac and extra-cardiac phenotypes, remarkably in contrast to those of ChAT tg. These ChATKD phenotypes again supported the findings from the previous studies [12], and further indicated that the NNCCS plays a crucial role in the heart and in the brain as its intrinsic self-defense mechanism. We previously established that the non-neuronal cardiac cholinergic system (NNCCS) is equipped with cardiomyocytes synthesizes acetylcholine (ACh), which is an indispensable endogenous system, sustaining cardiac homeostasis and regulating an inflammatory status, by transgenic mice overexpressing choline acetyltransferase (ChAT) gene in the heart. Whole body biological significances of NNCCS remain to be fully elucidated
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