Direct left ventricular wall stretch activates GATA4 binding in perfused rat heart: involvement of autocrine/paracrine pathways.
The signaling cascades that activate transcription factors during cardiac hypertrophy are largely unknown. To evaluate the mechanisms for GATA4 and activator protein-1 (AP-1) activation, isolated perfused rat hearts were exposed to elevated wall stretch by inflating a left ventricular balloon. Gel mobility shift assays were used to analyze the transacting factors that interact with the GATA or the AP-1 motifs of the B-type natriuretic peptide (BNP) promoter. Direct wall stretch for 30 min produced a twofold increase ( P<0.001) in left ventricular BNP GATA4- but not GATA5- and GATA6-binding activity. In addition, increased BNP AP-1-binding activity and the presence of c-fos were demonstrated in wall-stretch-stimulated ventricles compared with unloaded ventricles. The mixed endothelin-1 ETA/ETB receptor antagonist bosentan and the angiotensin II (Ang II) type 1 (AT1) receptor antagonist CV-11974 completely inhibited the wall-stretch-induced increase in left ventricular BNP GATA4 and AP-1 activity. Infusions of ET-1 and Ang II in the absence of wall stretch also stimulated BNP GATA4-binding activity ( P<0.01). These results show that ET-1 and Ang II are required for the stimulation of GATA4 and AP-1 DNA-binding activity in response to direct left ventricular wall stretch.
Hautala
Nina
N
Department of Pharmacology and Toxicology, Biocenter Oulu, 90014 University of Oulu, Finland.
Tenhunen
Olli
O
Szokodi
Istvan
I
Ruskoaho
Heikki
H
D000804:Angiotensin II / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D019898:Autocrine Communication / Q000502:physiology*; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D000077300:Bosentan; D002404:Catheterization; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D050991:GATA4 Transcription Factor; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D019899:Paracrine Communication / Q000502:physiology*; D010477:Perfusion; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016276:Ventricular Function
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004268:DNA-Binding Proteins; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D050991:GATA4 Transcription Factor; D012333:RNA, Messenger; D013449:Sulfonamides; D013777:Tetrazoles; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D000804:Angiotensin II; D000077300:Bosentan; C081643:candesartan