Modulation of Angiotensin II Signaling for GATA4 Activation by Homocysteine

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Abstract
Homocysteine (Hcy) is a redox active thiol-containing compound with pro-oxidant and pathogenic properties in the cardiovascular system. Angiotensin II (Ang II) also plays important roles in age-associated cardiovascular disease. Recently, the GATA4 transcription factor was recognized as a mediator of heart failure. We investigated the interrelationship of these elements in NIH/3T3 fibroblasts and found that Ang II induces GATA4 activity and Hcy alters Ang II signaling. Electrophoretic mobility shift assays determined that treatment of cells with Ang II induced DNA binding activity to the GATA consensus sequence. This activation was transient with a peak occurring at 30 min. Supershift analysis revealed the GATA binding protein as GATA4. Ang II also induced NFAT activity with similar kinetics. Pretreatment of cells with Hcy (100 μM) delayed the peak of Ang II-induced NFAT and GATA activation to 60 min. Ang II-mediated activation of c-fos serum response factor (SRF) was similarly delayed by Hcy. These results suggest the pathogenic mechanism of Hcy action may be mediated in part via modulation of Ang II-signaling for gene transcription.