Enhanced activity of the myocardial Na+/H+ exchanger contributes to left ventricular hypertrophy in the Goto-Kakizaki rat model of type 2 diabetes: critical role of Akt.
OBJECTIVE
Diabetes mellitus is a strong risk factor for the development of heart failure, and left ventricular (LV) hypertrophy has been detected in a significant proportion of diabetic patients. Because several studies have suggested that the Na(+)/H(+) exchanger (NHE1) plays a part in the molecular mechanisms involved in cardiac hypertrophy, we investigated its activity and its role in LV myocytes from the Goto-Kakizaki (GK) rat model of type 2 diabetes.


METHODS
Fluorometric measurements were used to assess sarcolemmal NHE1 activity in isolated myocytes. NHE1 levels and the possible molecular pathways driving and/or related to NHE1 activity were investigated in relation to the diabetic LV phenotype.


RESULTS
Enhanced NHE1 activity was associated with LV myocyte hypertrophy. This occurred in the absence of any change in NHE1 protein levels; however, activation of several molecular pathways related to NHE1 activity was demonstrated. Thus, phosphorylation of the extracellular signal-regulated protein kinase (Erk), of the protein kinase Akt (also known as protein kinase B) and of the Ca(2+)/calmodulin-dependent kinase II was increased in GK LV myocytes. Intracellular Ca(2+) levels were also increased. Chronic treatment (10-12 weeks) with the NHE1 inhibitor cariporide normalised NHE1 activity, decreased [Formula: see text] levels and reduced LV myocyte hypertrophy. Moreover, among the various activated pathways, cariporide treatment markedly reduced Akt activity only.


CONCLUSIONS
These findings indicate that activation of the Akt pathway represents a likely mechanism mediating the hypertrophic effect of increased NHE1 activity in the GK model of type 2 diabetes.
Darmellah
A
A
Marie Lannelongue Hospital, UMR CNRS 8078-University of Paris South XI, 133 Avenue de la Résistance, 92350 Le Plessis Robinson, France.
Baetz
D
D
Prunier
F
F
Tamareille
S
S
Rücker-Martin
C
C
Feuvray
D
D
D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004452:Echocardiography; D006339:Heart Rate; D018613:Microscopy, Confocal; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000503:physiopathology*
D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; D051057:Proto-Oncogene Proteins c-akt