Transcription factor MITF regulates cardiac growth and hypertrophy.
High levels of microphthalmia transcription factor (MITF) expression have been described in several cell types, including melanocytes, mast cells, and osteoclasts. MITF plays a pivotal role in the regulation of specific genes in these cells. Although its mRNA has been found to be present in relatively high levels in the heart, its cardiac role has never been explored. Here we show that a specific heart isoform of MITF is expressed in cardiomyocytes and can be induced by beta-adrenergic stimulation but not by paired box gene 3 (PAX3), the regulator of the melanocyte MITF isoform. In 2 mouse strains with different MITF mutations, heart weight/body weight ratio was decreased as was the hypertrophic response to beta-adrenergic stimulation. These mice also demonstrated a tendency to sudden death following beta-adrenergic stimulation. Most impressively, 15-month-old MITF-mutated mice had greatly decreased heart weight/body weight ratio, systolic function, and cardiac output. In contrast with normal mice, in the MITF-mutated mice, beta-adrenergic stimulation failed to induce B-type natriuretic peptide (BNP), an important modulator of cardiac hypertrophy, while atrial natriuretic peptide levels and phosphorylated Akt were increased, suggesting a cardiac stress response. In addition, cardiomyocytes cultured with siRNA against MITF showed a substantial decrease in BNP promoter activity. Thus, for what we believe is the first time, we have demonstrated that MITF plays an essential role in beta-adrenergic-induced cardiac hypertrophy.
Tshori
Sagi
S
Department of Biochemistry, Hebrew University Medical School, Jerusalem, Israel.
Gilon
Dan
D
Beeri
Ronen
R
Nechushtan
Hovav
H
Kaluzhny
Dmitry
D
Pikarsky
Eli
E
Razin
Ehud
E
D000818:Animals; D001835:Body Weight / Q000235:genetics; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D049108:Cell Enlargement / Q000187:drug effects; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006321:Heart / Q000254:growth & development*; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000502:physiology*; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D041681:NIH 3T3 Cells; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D009929:Organ Size / Q000235:genetics; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics
D051739:Microphthalmia-Associated Transcription Factor; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D034741:RNA, Small Interfering; D020097:Natriuretic Peptide, Brain; C068686:Pax3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D007545:Isoproterenol