Signaltransduktion der Angiotensin II-vermittelten Steigerung der TGF[beta]-Expression in adulten ventrikulären Kardiomyozyten

Abstract

Signal-transduction of the Angiotensin II-mediated increase of the TGF[beta]-expression in adult ventricular cardiomyocytes

The present study describes new important intracellular signaling procedure in ventricular cardiomyocytes which are involved for the angiotensin II dependent induction of TGF[beta] expression. TGF[beta] is a cytocine which increases the sensivity of cardiaomyocytes in other hypertrophic stimuli. The increased expression of TGF[beta] probably plays an important role in the development of a pathological cardiac hypertrophy, which results in heart failure.

This study shows that in combination with NAD(P)H-oxidase an initial redox sensitive procedure occurs after angiotensin II induction. There are two types of NAD(P)H-oxidase, which distinguishe themselves due to their subunits, - the vascular smooth muscle cell type and the neutrophil cell type. The NAD(P)H-oxidase of adult cardiomyocytes shares structural similarities with the smooth muscle type. The experiments further show that this redox sensitive step activates protein kinase C and a tyrosinkinase, which ist not further specified. The next step of this signal transduction pathway shows an increase in phosphorylation of p38 MAP-Kinase a member of the "mitogen activated protein kinases" after angiotensin II induction. An increase in phosphorylation indicates its activation. The activation of the p38 MAP-Kinase results in the activation of the transcription factor AP1 leading to the increased expression of TGF[beta].

The fact that a redox-sensitive step is a key element of the signal transduction from angiotensin II to TGF[beta] expression sheds new light on the role the myocardial redox state plays in the development of myocardial hyperthrophy. It can be assumed that an antioxidative therapy reduces the myocardial TGF[beta] expression and therefore the development of a pathological myocardial hypertrophy.