Pathways regulating Na+/Ca2+ exchanger expression in the heart.
The Na(+)/Ca(2+) exchanger (NCX1) is regulated at the transcriptional level in cardiac hypertrophy, ischemia, and failure. Following pressure overload, activation of MAPKs coincides with the kinetics of NCX1 gene upregulation in adult cardiocytes. Using adenoviral gene delivery, we begin to identify the molecular pathways responsible for upregulation of the exchanger gene. Inhibition of ERK with the MEK inhibitor UO126, the ERK protein phosphatase MKP-3, inhibited ERK activation, but only inhibited alpha-adrenergic-induced NCX1 upregulation by 30%. Overexpression of DN-JNK lowered basal NCX1 expression. Overexpression of activated MKK-3 was sufficient for alpha-adrenergic-stimulated upregulation of the reporter gene. Together, this data indicates that (1) JNK mediates basal cardiac expression of the NCX1 gene, (2) ERK and p38 play a role in alpha-adrenergic-stimulated NCX1 upregulation, and (3) p38 activation alone is sufficient for NCX1 upregulation.
Menick
Donald R
DR
Gazes Cardiac Research Institute, Medical University of South Carolina, Charleston, South Carolina 29425, USA. menickd@musc.edu
Xu
Lin
L
Kappler
Christina
C
Jiang
Wenjing
W
Withers
Patrick
P
Shepherd
Neal
N
Conway
Simon J
SJ
Müller
Joachim G
JG
D020121:5' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002415:Cats; D004195:Disease Models, Animal; D005091:Exons; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology*; D016023:Integrins / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D032342:Muscle Cells / Q000502:physiology; D011401:Promoter Regions, Genetic; D012326:RNA Splicing; D019831:Sodium-Calcium Exchanger / Q000235:genetics*
D020121:5' Untranslated Regions; D016023:Integrins; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases