Transcription factor AP-2α triggers apoptosis in cardiac myocytes

Abstract

Idiopathic-dilated cardiomyopathy (IDC) is a common primary myocardial disease of unknown etiology associated with apoptosis, cardiac dilatation, progressive heart failure and increased mortality. An elevation of the transcription factor activator protein 2a (AP-2a) is involved in vertebrate embryonic development and oncogenesis. Here, we show that AP-2a protein is expressed in the human heart and increased in human failing myocardium with IDC. Adenovirusmediated overexpression of human AP-2a triggered apoptosis and increased mRNA levels of Bcl-2 family members Bax and Bcl-x in rat cardiomyocytes. Immunohistological analysis of human myocardium revealed an increased percentage of AP-2a-positive nuclei in IDC and, interestingly, a colocalization of AP-2a-positive but not -negative cells with a caspasecleaved fragment of poly(ADP-ribose)polymerase. We suggest AP-2a as a novel cardiac regulator implicated in the activation of apoptosis in IDC.

Development of an inducible gene expression system for primary murine keratinocytes

“…AP-2α is a transcription factor that plays an important role in keratinocyte growth and differentiation [22]. It has been difficult till now to stably express AP-2α in cultured cells because of its deleterious effect on cell survival [23]. Thus, our studies provide proof of principle for the notion that potent or potentially toxic proteins can be inducibly expressed in mouse keratinocytes.…”

“…In keratinocytes, AP-2α functions in developmental events associated with growth and differentiation and plays a key role in keratinocyte specific gene expression [22,33]. The presence of supra-physiological levels of AP-2α has been shown to block cell cycle progression [34] and induce cellular apoptosis [23,35]; thus evading attempts at stable transfection. Consequently overexpression studies of AP-2α in cell culture model systems have been limited to transient transfections.…”

Cardiac phenylethanolamine N-methyltransferase: localization and regulation of gene expression in the spontaneously hypertensive rat

“…These expression differences may be due to activation of several different intracellular signaling pathways involved in stimulating these transcription factors. Interestingly, AP-2 has been identified as a novel cardiac regulator of apoptosis in idiopathic-dilated cardiomyopathy in rat cardiomyoctyes and several studies support the hypothesis that chronic β-adrenergic stimulation of the cAMP-dependent signaling pathway by elevated CAs contributes to the altered expression of functionally relevant cardiac genes in the failing heart (Müller et al, 2004;Müller et al, 2000). Therefore, the changes in the transcriptional regulators of PNMT observed in the SHR D r a f t heart may be linked to the altered adrenergic function previously noted in SHR.…”

Regulation of heterotrimeric G-protein signaling by NDPK/NME proteins and caveolins: an update

“…39,49 The increased NDPK-C mRNA levels during long-term β-adrenoceptor stimulation might be due to activation of AP-2-and CREBP-binding sites in the mouse nme3 gene, which can regulate gene expression depending on cAMP levels. 50,51 Indeed, both patients and isoprenaline-stimulated rats treated with β-blockers showed a reduced NDPK content at the plasma membrane. 52 The increased NDPK expression in heart failure and the stimulatory effect of NDPKs on cAMP and contractility in animal models appear at odds with the decreased cAMP levels and impaired contractility in heart failure.…”