Pressure overload increases GATA4 binding activity via endothelin-1.

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Gene Regulation

Background:

• Signaling pathways controlling cardiac myocyte hypertrophy during hemodynamic overload are not fully understood.
• GATA4, a cardiac-restricted transcription factor, regulates genes like B-type natriuretic peptide (BNP) in hypertrophied hearts.

Purpose of the Study:

• To investigate the signaling mechanisms for GATA transcription factor activation in response to pressure overload in vivo.
• To identify the role of endothelin-1 (ET-1) and angiotensin II in regulating GATA4 activity during cardiac pressure overload.

Main Methods:

• An in vivo rat model using arginine(8)-vasopressin (AVP) to induce pressure overload.
• Gel mobility shift assays to analyze transcription factor binding to the BNP promoter.
• Administration of endothelin-1 receptor antagonist bosentan and angiotensin II type 1 receptor antagonist losartan.

Main Results:

• AVP-induced pressure overload increased BNP and c-fos mRNA levels but not GATA4 or GATA6 mRNA.
• Pressure overload significantly increased GATA4 DNA binding activity in the left ventricle.
• Bosentan, but not losartan, completely inhibited the pressure overload-induced increase in GATA4 binding activity.

Conclusions:

• Endothelin-1 (ET-1) acts as a signaling molecule that rapidly upregulates GATA4 DNA binding activity in response to pressure overload.
• This rapid upregulation of GATA4 binding activity is a key event in the cardiac hypertrophic response to pressure overload.