Abstract
Intrinsic cardiac adrenergic (ICA) cells regulate both developing and adult cardiac physiological and pathological processes. However, the role of ICA cells in septic cardiomyopathy is unknown. Here we show that norepinephrine (NE) secretion from ICA cells is increased through activation of Toll-like receptor 4 (TLR4) to aggravate myocardial TNF-α production and dysfunction by lipopolysaccharide (LPS). In ICA cells, LPS activated TLR4-MyD88/TRIF-AP-1 signaling that promoted NE biosynthesis through expression of tyrosine hydroxylase, but did not trigger TNF-α production due to impairment of p65 translocation. In a co-culture consisting of LPS-treated ICA cells and cardiomyocytes, the upregulation and secretion of NE from ICA cells activated cardiomyocyte β1-adrenergic receptor driving Ca2+/calmodulin-dependent protein kinase II (CaMKII) to crosstalk with NF-κB and mitogen-activated protein kinase pathways. Importantly, blockade of ICA cell-derived NE prevented LPS-induced myocardial dysfunction. Our findings suggest that ICA cells may be a potential therapeutic target for septic cardiomyopathy.