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(Circulation Research. 2009;105:422.)
© 2009 American Heart Association, Inc.

Molecular Medicine

Angiotensin II–Inducible Smooth Muscle Cell Apoptosis Involves the Angiotensin II Type 2 Receptor, GATA-6 Activation, and FasL-Fas Engagement

Nicole Y. Tan, Jian-Mei Li, Roland Stocker, Levon M. Khachigian

From the Centre for Vascular Research (N.Y.T., J.-M.L., L.M.K.), University of New South Wales, Sydney; and Centre for Vascular Research, University of Sydney (R.S.), Australia.

Correspondence to Levon M. Khachigian, PhD, DSc, Centre for Vascular Research, University of New South Wales, Sydney NSW 2052, Australia. E-mail L.Khachigian{at}unsw.edu.au

Rationale: Fas ligand (FasL)-mediated smooth muscle cell (SMC) apoptosis within the vulnerable plaque may lead to plaque instability and rupture, events that underlie myocardial infarction and stroke.

Objective: The molecular mechanisms underlying FasL transcription and FasL-dependent SMC apoptosis were investigated in this study in vitro and in vivo.

Methods and Results: We demonstrate that GATA-6, the predominant GATA family member expressed in SMCs, stimulates SMC apoptosis in an extracellular FasL-dependent manner. Both GATA-6 and FasL were inducibly and transiently expressed following balloon injury to rat carotid arteries. We identified two potential GATA binding in the FasL promoter and demonstrated using DNA binding and chromatin immunoprecipitation assays that GATA-6 regulates FasL through one (^–298TTATCA^–303) but not both these elements. Angiotensin II (Ang II) stimulated expression of both GATA-6 and FasL. Ang II increased SMC apoptosis in an Ang II type 2 receptor–, caspase 8–, and FasL-dependent fashion. GATA-6 activation was MEK-ERK1/2– and JNK-dependent, and GATA-6 small interfering RNA blocked Ang II–inducible FasL expression and SMC apoptosis. Administration of Ang II to rats increased FasL expression and apoptosis in carotid artery SMCs in an Ang II type 2 receptor– and GATA-6–dependent manner.

Conclusions: This study provides new insights into the transcriptional events underpinning FasL-dependent SMC apoptosis after exposure to Ang II.

Key Words: Fas ligand • GATA-6 • apoptosis • angiotensin II