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Assessment of Sarcoplasmic Reticulum Calcium Reserve and Intracellular Diastolic Calcium Removal in Isolated Ventricular Cardiomyocytes
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Ceramide-mediated depression in cardiomyocyte contractility through PKC activation and modulation of myofilament

Jillian N Simon1, Shamim A K Chowdhury, Chad M Warren

  • 1Department of Physiology and Biophysics and Center for Cardiovascular Research, College of Medicine, University of Illinois, Chicago, IL, 60612, USA.

Basic Research in Cardiology
|October 5, 2014
PubMed

Insights

Elevated ceramides impair heart muscle contractility by altering protein phosphorylation, leading to cardiac dysfunction. This study reveals a novel mechanism linking ceramide accumulation to heart disease through protein kinase C (PKC) signaling.

Area of Science:

  • Cardiovascular Biology
  • Cellular Physiology
  • Molecular Cardiology

Background:

  • Ceramide accumulation is linked to cardiac disorders like heart failure and ischemia-reperfusion injury.
  • The specific role of ceramides in modulating cardiac contractility remains poorly understood.
  • Understanding ceramide's impact on cardiomyocyte function is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the functional consequences of acute ceramide exposure on adult rat cardiomyocytes.
  • To elucidate the signaling pathways, particularly protein kinase C (PKC), involved in ceramide-induced contractile dysfunction.
  • To identify specific myofilament proteins phosphorylated by PKC in response to ceramide.

Main Methods:

  • Isolated adult rat cardiomyocytes were acutely exposed to C6-ceramide.
  • Myocyte shortening, intracellular calcium ([Ca(2+)]i) transients, and protein phosphorylation were measured.
  • Techniques included field stimulation, 2D electrophoresis, and phospho-peptide antibodies.

Main Results:

  • C6-ceramide significantly depressed cardiomyocyte shortening amplitude and velocity without affecting intracellular calcium.
  • PKCε activation was implicated in the ceramide-induced effects.
  • Ceramide treatment increased phosphorylation of myosin binding protein-C (cMyBP-C) and troponin I (cTnI) in a PKC-dependent manner.

Conclusions:

  • Acute ceramide exposure impairs cardiomyocyte contractility by altering myofilament response to calcium.
  • PKC-dependent phosphorylation of cMyBP-C and cTnI contributes to this contractile dysfunction.
  • These findings highlight a novel mechanism linking ceramide accumulation to cardiac disease pathophysiology.

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