Ceramide-mediated depression in cardiomyocyte contractility through PKC activation and modulation of myofilament protein phosphorylation Journal Article

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Authors: Simon, J. N.; Chowdhury, S. A.; Warren, C. M.; Sadayappan, S; Wieczorek, D. F.; Solaro, R. J.; Wolska, B. M.
Article Title: Ceramide-mediated depression in cardiomyocyte contractility through PKC activation and modulation of myofilament protein phosphorylation
Abstract: Although ceramide accumulation in the heart is considered a major factor in promoting apoptosis and cardiac disorders, including heart failure, lipotoxicity and ischemia-reperfusion injury, little is known about ceramide's role in mediating changes in contractility. In the present study, we measured the functional consequences of acute exposure of isolated field-stimulated adult rat cardiomyocytes to C6-ceramide. Exogenous ceramide treatment depressed the peak amplitude and the maximal velocity of shortening without altering intracellular calcium levels or kinetics. The inactive ceramide analog C6-dihydroceramide had no effect on myocyte shortening or [Ca(2+)]i transients. Experiments testing a potential role for C6-ceramide-mediated effects on activation of protein kinase C (PKC) demonstrated evidence for signaling through the calcium-independent isoform, PKCepsilon. We employed 2-dimensional electrophoresis and anti-phospho-peptide antibodies to test whether treatment of the cardiomyocytes with C6-ceramide altered myocyte shortening via PKC-dependent phosphorylation of myofilament proteins. Compared to controls, myocytes treated with ceramide exhibited increased phosphorylation of myosin binding protein-C (cMyBP-C), specifically at Ser273 and Ser302, and troponin I (cTnI) at sites apart from Ser23/24, which could be attenuated with PKC inhibition. We conclude that the altered myofilament response to calcium resulting from multiple sites of PKC-dependent phosphorylation contributes to contractile dysfunction that is associated with cardiac diseases in which elevations in ceramides are present.
Journal Title: Basic research in cardiology
Volume: 109
Issue: 6
ISSN: 1435-1803; 0300-8428
Publisher: Unknown  
Journal Place: Germany
Date Published: 2014
Start Page: 445
End Page: 014-0445-6. Epub 2014 Oct 4
Language: eng
DOI/URL:

10.1007/s00395-014-0445-6
Notes: GR: K02 HL-114749/HL/NHLBI NIH HHS/United States; GR: P01 HL-62426/HL/NHLBI NIH HHS/United States; GR: R01 HL-081680/HL/NHLBI NIH HHS/United States; GR: R01 HL-105826/HL/NHLBI NIH HHS/United States; GR: R01 HL-64035/HL/NHLBI NIH HHS/United States; JID: 0360342; 2013/01/29 [received]; 2014/09/26 [accepted]; 2014/09/25 [revised]; 2014/10/04 [aheadofprint]; ppublish