The MKK6-p38 MAPK pathway prolongs the cardiac contractile calcium transient, downregulates SERCA2, and activates NF-AT

Catherine Andrews, Peter D. Ho, Wolfgang H. Dillmann, Christopher C. Glembotski, Patrick M. McDonough

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Objective: Our goal was to determine if the MKK6-p38 MAPK pathway regulates cardiac intracellular calcium ([Ca2+]i). We also tested if MKK6 might influence expression of SERCA2, a calcium regulatory molecule involved in relaxation, and the activity of nuclear factor of activated T-cells (NF-AT), a calcium-regulated transcription factor that participates in pathological responses to pressure-overload. Methods: Neonatal rat ventricular myocytes were transfected with MKK6(Glu), an activator of p38 MAPK. Green fluorescent protein (GFP) was used as transfection marker and [Ca2+]i was evaluated via indo-1. SERCA2 expression was assayed via Northern and Western techniques. The activity of the rat SERCA2 gene promoter and NF-AT-dependent gene expression were monitored with reporter genes. Myocyte contractility was regulated by electrical pacing. Results: MKK6(Glu) prolonged decay of the contractile calcium transients, downregulated SERCA2 expression, and reduced the activity of the rat SERCA2 gene promoter. Diastolic [Ca2+]i in myocytes pacing at 1-2 Hz was dramatically increased by MKK6(Glu). NF-AT-dependent gene expression was activated by MKK6(Glu) and by pacing of contractions in a synergistic manner. Overexpression of SERCA2 mitigated the effects of MKK6(Glu) on [Ca2+]i and NF-AT. Conclusions: The MKK6(Glu)-p38 MAPK pathway prolongs the decay phase of the cardiac contractile calcium by downregulating SERCA2, increasing diastolic [Ca2+]i which activates NF-AT. The ability of SERCA2 over-expression to reduce NF-AT activity represents a potential novel therapeutic effect of SERCA2 that should be further considered in the development of cardiac gene therapy strategies.

Original languageEnglish (US)
Pages (from-to)46-56
Number of pages11
JournalCardiovascular research
Issue number1
StatePublished - Jul 1 2003
Externally publishedYes


  • Ca-pump
  • Calcium (cellular)
  • Gene expression
  • Gene therapy
  • Signal transduction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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