Adrenomedullin Gene Expression Is Developmentally Regulated and Induced by Hypoxia in Rat Ventricular Cardiac Myocytes

Abstract

Adrenomedullin is a recently discovered hypotensive peptide that is expressed in a variety of cell and tissue types. Using the technique of differential display, the adrenomedullin gene was observed to be differentially expressed in developing rat heart. Reverse transcription-polymerase chain reaction analysis revealed that the level of adrenomedullin mRNA was significantly higher in adult ventricular cardiac muscle as compared with embryonic day 17 ventricular cardiac muscle. Adrenomedullin receptor mRNA was constitutively expressed throughout development of the ventricular heart. Two potential hypoxia-inducible factor-1 (HIF-1) consensus binding sites were identified in the mouse adrenomedullin promoter at -1095 and -770 nucleotides from the transcription start site. Exposure of cultured adult rat ventricular cardiac myocytes to hypoxia (1% O 2 ) resulted in a significant, time-dependent increase in adrenomedullin mRNA levels. Transfection studies revealed that the 5-flanking sequence of adrenomedullin was capable of mediating a hypoxia-inducible increase in transcription. Mutation of the putative HIF-1 consensus binding sites revealed that the major regulatory sequence that mediates the hypoxia-inducible transcriptional response is located at -1095. These data demonstrate that the adrenomedullin gene is developmentally regulated in ventricular cardiomyocytes, that adrenomedullin transcription can be induced by hypoxia, and that this response is primarily mediated by HIF-1 consensus sites in the adrenomedullin promoter.

Identification of molecular apocrine breast tumours by microarray analysis

“…The poor survival of the patients with the molecular apocrine profile in the Sorlie and van't Veer studies (Figure 5b) is consistent with the poor prognosis expected for ER-negative, ERBB2-positive tumours. The gene cluster shared by the basal and molecular apocrine tumours (Figure 1c panel 3) includes several genes induced by hypoxia, including ERO1L, ADM and NDRG1 (Cormier-Regard et al, 1998;Park et al, 2000;Gess et al, 2003), which would again be consistent with a poor prognosis. Taken together, these data suggest that the molecular apocrine profile does not identify only patients with classical apocrine carcinomas.…”

Tamoxifen induction of angiogenic factor expression in endometrium

“…Both ADM and bFGF are known to be upregulated by hypoxia (Cormier-Regard et al, 1998;Nakayama et al, 1998;Le and Corry, 1999;Nguyen and Claycomb, 1999;Garayoa et al, 2000). TAM has been shown to induce hypoxia in MCF-7 xenografts (Evans et al, 1997).…”

Adrenomedullin inhibits hypoxic cell death by upregulation of Bcl-2 in endometrial cancer cells: a possible promotion mechanism for tumour growth

“…Recently, ADM has been reported to be upregulated by hypoxia (Cormier-Regard et al, 1998;Nakayama et al, 1998). Expression was shown to be under hypoxiainducible transcription factor-1 (HIF-1) regulation similar to that of classic oxygen-regulated genes such as erythropoietin (Epo) or vascular endothelial growth factor (VEGF) (Garayoa et al, 2000;Nguyen and Claycomb, 1999).…”