Regulation of the rat atrial natriuretic peptide gene after acute imposition of left ventricular pressure overload

被引:40
作者
Cornelius, T
Holmer, SR
Müller, FU
Riegger, GAJ
Schunkert, H
机构
[1] Univ Regensburg, Klin & Poliklin Innere Med 2, D-93042 Regensburg, Germany
[2] Univ Munster, Inst Pharmakol & Toxikol, D-4400 Munster, Germany
关键词
atrial natriuretic peptide; gene regulation; activator protein-1; c-fos; gene transfection; heart;
D O I
10.1161/01.HYP.30.6.1348
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
The upregulation of left ventricular (LV) atrial natriuretic peptide (ANP) mRNA is a highly conserved marker of cardiac hypertrophy. The aim of this study was to further examine the pathway leading to ANP induction during pressure overload of the heart. Systolic wall stress was imposed acutely on isovolumetrically beating rat hearts in a Langendorff apparatus (sigma=300x10(3) dyne/cm(2)). Northern and Western blots revealed that elevated wall stress induced LV c-fos and c-jun mRNAs (3.5- and 3-fold, P<.05 after 60 minutes), c-Fos and c-Jun proteins (3.9- and 4.3-fold, P<.05 after 120 minutes), as well as ANP mRNA.(2.2-fold, P<.05 after 120 minutes). ANP upregulation was prevented by inhibition of protein synthesis (cycloheximide). Electrophoresis mobility shift assays were performed to link c-Fos and c-Jun (ie, components of the heterodimeric transcription factor AP-1) and ANP induction. A putative AP-1 binding site within the rat ANP promoter (nucleotides-512 to -473) bound specifically to of wall stress-stimulated hearts. Antibodies directed against c-Fos protein resulted in a shift of this DNA/protein complex, suggesting physical interaction between AP-1 and the ANP promoter. Myocardial transfection of promoter constructs revealed that after acute imposition of wall stress, this AP-1 site enhanced a reporter gene (8- to 10-fold compared with a minimal promoter, P<.05). Interestingly, nuclear extracts of stimulated hearts as well as pure AP-1 protein bound to a putative CRE site (nucleotides -613 to -584) as well. Like the AP-1 site, this cAMP-responsible element (CRE) site was found to enhance the transfected ANP promoter/reporter gene significantly (17.5-fold, P<.05), Mutation of either AP-1 or CRE sites did not decrease reporter gene activity, whereas mutation of both resulted in loss of inducibility. These experiments suggest that LV ANP-regulation after acute wall stress includes the activation of AP-1 and/or CRE cis acting elements. However, the transient nature of c-fos and c-jun upregulation also suggests that AP-1 is not the only mediator of ANP induction in LV hypertrophy.
引用
收藏
页码:1348 / 1355
页数:8
相关论文
共 42 条
[1]  
ARGENTIN S, 1991, J BIOL CHEM, V266, P23315
[2]  
ARGENTIN S, 1985, J BIOL CHEM, V260, P4568
[3]   VITAMIN-D RECEPTORS IN HEART - EFFECTS ON ATRIAL-NATRIURETIC-FACTOR [J].
BIDMON, HJ ;
GUTKOWSKA, J ;
MURAKAMI, R ;
STUMPF, WE .
EXPERIENTIA, 1991, 47 (09) :958-962
[4]   NEONATAL ATRIA AND VENTRICLES SECRETE ATRIAL-NATRIURETIC-FACTOR VIA TISSUE-SPECIFIC SECRETORY PATHWAYS [J].
BLOCH, KD ;
SEIDMAN, JG ;
NAFTILAN, JD ;
FALLON, JT ;
SEIDMAN, CE .
CELL, 1986, 47 (05) :695-702
[5]  
BRASIER AR, 1989, BIOTECHNIQUES, V7, P1116
[6]   BLOCKADE OF THE RENIN-ANGIOTENSIN SYSTEM IN CARDIAC PRESSURE-OVERLOAD HYPERTROPHY IN RATS [J].
BRUCKSCHLEGEL, G ;
HOLMER, SR ;
JANDELEIT, K ;
GRIMM, D ;
MUDERS, F ;
KROMER, EP ;
RIEGGER, GAJ ;
SCHUNKERT, H .
HYPERTENSION, 1995, 25 (02) :250-259
[7]   REGULATION OF CARDIAC GENE-EXPRESSION DURING MYOCARDIAL GROWTH AND HYPERTROPHY - MOLECULAR STUDIES OF AN ADAPTIVE PHYSIOLOGICAL-RESPONSE [J].
CHIEN, KR ;
KNOWLTON, KU ;
ZHU, H ;
CHIEN, S .
FASEB JOURNAL, 1991, 5 (15) :3037-3046
[8]  
GLEMBOTSKI CC, 1993, J BIOL CHEM, V268, P20646
[9]   Stabilization of the B-type natriuretic peptide mRNA in cardiac myocytes by alpha-adrenergic receptor activation: Potential roles for protein kinase C and mitogen-activated protein kinase [J].
Hanford, DS ;
Glembotski, CC .
MOLECULAR ENDOCRINOLOGY, 1996, 10 (12) :1719-1727
[10]   PROTOONCOGENE INDUCTION AND REPROGRAMMING OF CARDIAC GENE-EXPRESSION PRODUCED BY PRESSURE OVERLOAD [J].
IZUMO, S ;
NADALGINARD, B ;
MAHDAVI, V .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1988, 85 (02) :339-343