Restoration of defective L-type Ca2+ current in cardiac myocytes of type 2 diabetic db/db mice by Akt and PKC-ι.
J Cardiovasc Pharmacol
; 58(4): 439-45, 2011 Oct.
Article
em En
| MEDLINE
| ID: mdl-21753738
ABSTRACT
Diabetes is associated with an increased risk of heart failure and the development of a cardiomyopathy whose etiology is only partially understood. Ca entry through the voltage-dependent L-type Ca channel CaV1.2 initiates the contractile cycle in cardiac myocytes. Decreased cardiac contractility and depressed CaV1.2 function have been reported in obese type 2 diabetic db/db mice. Here, we demonstrate that a reduction in phosphoinositide 3-kinase (PI3K) signaling is a major contributor to the altered function of CaV1.2 in db/db cardiac myocytes. Using the whole-cell patch clamp technique, we determined that intracellular infusion of cardiac myocytes from db/db mice with phosphatidylinositol 3,4,5-trisphosphate (PIP3), the second messenger produced by PI3K, increased the L-type Ca current (ICa,L) density nearly to the level seen in wild-type cells. PIP3 also reversed the positive shift in the voltage dependence of the steady-state current activation observed in db/db myocytes. Infusion of protein kinases that act downstream of PI3K also affected ICa,L. Akt1 and Akt2 were as effective as PIP3 in restoring the ICa,L density in db/db myocytes but did not affect the voltage dependence of current activation. The infusion of atypical PKC-ι (the human homolog of mouse PKC-λ) caused a small but significant increase in the ICa,L density and completely reversed the shift in voltage dependence of steady-state current activation. These results indicate that a defect in PI3K/PIP3/Akt/PKC-λ signaling is mainly responsible for the depressed CaV1.2 function in the hearts of db/db mice with type 2 diabetes.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteína Quinase C
/
Canais de Cálcio Tipo L
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Diabetes Mellitus Tipo 2
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Proteínas Proto-Oncogênicas c-akt
/
Isoenzimas
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
J Cardiovasc Pharmacol
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Estados Unidos