Soluble CD14 inhibits contractile function and insulin action in primary adult rat cardiomyocytes.
Epicardial adipose tissue (EAT) from patients with type 2 diabetes (T2D) is characterized by monocyte infiltrations and displays an elevated release of the monocyte marker soluble cluster of differentiation 14 (sCD14) versus EAT from patients without T2D. We propose that an increased abundance of sCD14 in EAT from patients with T2D may impair the function and insulin sensitivity of the adjacent cardiomyocytes. To examine this, primary adult rat cardiomyocytes were incubated with increasing concentrations of sCD14 in the presence and absence of the co-receptor lipopolysaccharide (LPS), and analyzed for effects on determinants of contractile function, activation of inflammation signalling and insulin action. Exposing cardiomyocytes to sCD14 increased the phosphorylation of the stress kinases p38 and extracellular-signal regulated kinase (ERK). In contrast, insulin-mediated phosphorylation of Akt on Thr308 and Ser473 was inhibited. Furthermore, sCD14 impaired sarcomere shortening and cytosolic Ca2+-fluxes. All responses were concentration-dependent and became significant at 1ng/ml sCD14. LPS, either alone or in complex with sCD14, did not affect contractile function or the activation of stress kinases and insulin signalling pathways. Similar data on protein phosphorylation were obtained when exposing human umbilical vein endothelial cells to sCD14. Finally, pharmacological inhibition of p38 reversed the detrimental effects of sCD14 on contractile function, but not on sCD14-induced insulin resistance. Collectively, these data show that sCD14 impairs the function and insulin sensitivity of cardiomyocytes, suggesting that an enhanced sCD14 release from EAT in patients with T2D may contribute to the pathogenesis of diabetes-related cardiometabolic complications.
Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany; German Center for Diabetes Research (DZD), München, Neuherberg, Germany.
Sabrina
S
Overhagen
Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany; German Center for Diabetes Research (DZD), München, Neuherberg, Germany.
Marcel
M
Blumensatt
Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany; German Center for Diabetes Research (DZD), München, Neuherberg, Germany.
Pia
P
Fahlbusch
Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany; German Center for Diabetes Research (DZD), München, Neuherberg, Germany.
Daniella
D
Herzfeld de Wiza
Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany; German Center for Diabetes Research (DZD), München, Neuherberg, Germany.
Heidi
H
Müller
Department of Cardiovascular Surgery, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany.
Bujar
B
Maxhera
Department of Cardiovascular Surgery, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany.
Payam
P
Akhyari
Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany; German Center for Diabetes Research (DZD), München, Neuherberg, Germany; Department of Endocrinology, Ghent University Hospital, Ghent, Belgium. Electronic address: margriet.ouwens@ddz.uni-duesseldorf.de.
D Margriet
DM
Ouwens
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008297:Male; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D011917:Rats, Inbred Lew; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D007328:Insulin; D018950:Lipopolysaccharide Receptors; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium
CD14; Cardiomyocytes; Contractile function; Insulin resistance; p38