Dominant-negative c-Jun inhibits rat cardiac hypertrophy induced by angiotensin II and hypertension.
Cardiac activator protein-1 (AP-1), composed of c-Jun, is significantly activated by hypertension or angiotensin II (AngII). This study was undertaken to elucidate whether c-Jun could be the potential target for treatment of cardiac hypertrophy. We constructed recombinant adenovirus carrying dominant-negative mutant of c-Jun (Ad.DN-c-Jun). Using catheter-based technique of adenoviral gene transfer, we achieved global myocardial transduction of DN-c-Jun in rats, to specifically inhibit cardiac AP-1. (1) AngII (200 ng/kg/min) infusion in rats caused cardiac hypertrophy, increased cardiac p70S6 kinase activity by 1.3-fold (P<0.05) and enhanced the gene expression of cardiac hypertrophic markers. Ad.DN-c-Jun, which was transferred to the heart 2 days before AngII infusion, prevented cardiac hypertrophy (P<0.01), decreased p70S6 kinase phosphorylation (P<0.05), and suppressed cardiac gene expression of brain natriuretic peptide, collagen I, III, and IV, monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) (P<0.01). (2) In genetically hypertensive rats with cardiac hypertrophy, cardiac gene transfer of Ad.DN-c-Jun, without affecting hypertension, regressed cardiac hypertrophy (P<0.05), and suppressed p70S6 kinase phosphorylation by 20% (P<0.05) and suppressed the enhanced expression of collagen I, III, and IV, MCP-1 and PAI-1. These results provided the first evidence that in vivo blockade of cardiac c-Jun inhibits pathologic cardiac hypertrophy.
Kim-Mitsuyama
S
S
Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan. kimmitsu@gpo.kumamoto-u.ac.jp
Izumi
Y
Y
Izumiya
Y
Y
Namba
M
M
Yoshida
K
K
Wake
R
R
Yoshiyama
M
M
Iwao
H
H
D000256:Adenoviridae / Q000235:genetics; D000804:Angiotensin II / Q000009:adverse effects / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D018932:Chemokine CCL2 / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D017353:Gene Deletion; D005799:Genes, Dominant; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006973:Hypertension / Q000150:complications / Q000378:metabolism; D007267:Injections; D008297:Male; D023421:Models, Animal; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000378:metabolism
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D024042:Collagen Type I; D024061:Collagen Type III; D024141:Collagen Type IV; D017395:Plasminogen Activator Inhibitor 1; D018808:Transcription Factor AP-1; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain; D038762:Ribosomal Protein S6 Kinases, 70-kDa