Angiotensin II-dependent loss of cardiac function: mechanisms and pharmacological targets attenuating this effect.
Pharmacological inhibition of components of the renin-angiotensin-system is one of the major therapeutically options to treat patients with heart failure. This study hypothesized that angiotensin II (Ang II) directly depresses contractile function (cell shortening) by activation of transforming growth factor-beta(1) (TGF-beta(1)). Moreover, we hypothesized that an inhibition of glycogen synthase kinase 3-betaGSK will compensate for this depressive effect by increasing SERCA2 expression. Isolated adult ventricular rat cardiomyocytes were used and cultured in the presence of Ang II (100 nM) for 24 h. Cell shortening and contractile dynamics were recorded at 2 Hz. Immunoblot techniques and gel mobility shift assays were used to demonstrate NFAT activation caused by inhibition of GSK and to demonstrate increases in the expression of SERCA2. Ang-II caused a nearly 20% decrease in cell shortening. This Ang II-dependent effect was mimicked by TGF-beta(1) (10 ng/ml), attenuated by addition of aprotinin, that was used to block the proteolytic activation of TGF-beta(1), or by application of a neutralizing antibody directed against TGF-beta(1). Inhibition of GSK activated NFAT, increased SERCA2 expression and improved cell function. In conclusion, the study identified a paracrine mechanism for the Ang II-dependent loss of cardiac function that occurs independently of hemodynamic changes. Furthermore, it characterized the differences between Ang II and alpha-adrenoceptor stimulation with respect to the maintenance of cellular function explaining cellular events contributing to the difference between adaptive (physiological) and mal-adaptive (patho-physiological) hypertrophy.
Mufti
Solaiman
S
Physiologisches Institut, Giessen, Germany.
Wenzel
Sibylle
S
Euler
Gerhild
G
Piper
Hans Michael
HM
Schlüter
Klaus-Dieter
KD
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000187:drug effects / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
C506948:Atp2a2 protein, rat; D050778:NFATC Transcription Factors; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D038362:Glycogen Synthase Kinase 3; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases