Abstract

Sympathetic neurons (SNs) regulate heart rate, conduction velocity, contractility and relaxation of the myocardium. Disruption of SNs in adult cardiac disease, leads to arrhythmias, myocardial dysfunction and sudden cardiac death. However, the role of SNs during cardiac development and whether disruption of cardiac SNs at embryonic stages is associated with disease progression in adult life is unknown. Moreover, controversy exists regarding the effect of SNs on neonatal myocardial regeneration after injury. As the heart is innervated by SNs from mid-gestation and the innervation continues through the neonatal stage, we generated genetically modified mice with profoundly reduced cardiac-specific sympathetic innervation starting at embryonic stages. Inhibition of sympathetic innervation resulted in larger heart size with increased number of myocytes that were smaller and more mononuclear. Analysis also confirmed increased cardiomyocyte proliferation. Interestingly, transcriptomic analysis of P7 and P14 hearts verified dysregulated cell cycle, calcium homeostasis and circadian genes. Remarkably, this led to persistently increased heart size and reduced function at adult stages. To investigate the mechanism whereby SNs, affect cardiomyocyte proliferation, we first co-cultured human stem cell-derived or mouse cardiomyocytes with ganglionic SNs and confirmed similar gene expression patterns. Moreover, alpha1 and beta2-specific adrenergic receptor agonists and norepinephrine, reduced cell cycle genes and myocyte proliferation and upregulated circadian genes such as Period1 and Period2. As circadian genes have been linked with regulation of cell cycle and apoptosis, we analyzed neonatal hearts from Period1/Period2 DKO mice and curiously discovered increased heart size, cardiomyocyte proliferation and cell cycle genes, and suppression of the Wee1 kinase an inhibitor of cell mitosis. More importantly, norepinephrine did not alter cardiomyocyte proliferation and cell cycle genes in Period1/Period2 DKO myocytes. To our knowledge this is the first study to provide direct evidence of the effect of SNs in the regulation of circadian genes in the heart and their role on neonatal cardiomyocyte proliferation.

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