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Transcription factor MITF regulates cardiac growth and hypertrophy
Sagi Tshori, … , Eli Pikarsky, Ehud Razin
Sagi Tshori, … , Eli Pikarsky, Ehud Razin
Published October 2, 2006
Citation Information: J Clin Invest. 2006;116(10):2673-2681. https://doi.org/10.1172/JCI27643.
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Research Article Cardiology

Transcription factor MITF regulates cardiac growth and hypertrophy

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Abstract

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 β-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 β-adrenergic stimulation. These mice also demonstrated a tendency to sudden death following β-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, β-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 β-adrenergic–induced cardiac hypertrophy.

Authors

Sagi Tshori, Dan Gilon, Ronen Beeri, Hovav Nechushtan, Dmitry Kaluzhny, Eli Pikarsky, Ehud Razin

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Figure 1

MITF is expressed in cardiomyocytes.

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MITF is expressed in cardiomyocytes.
(A) Structure of MITF protein. The ...
(A) Structure of MITF protein. The ce/ce mutation is a stop codon between the bHLH and the leucine zipper. b, basic domain; zip, leucine zipper. Also shown is a schematic representation of MITF protein products, with different N termini and common C terminus. (B) Genomic organization of the mi locus. tg/tg mice have an insertion of about 50 copies of a transgene incorporated into the promoter region of MITF. Filled boxes represent alternative promoters. Arrow indicates tg/tg insertion site. (C) Western blot analysis of heart, liver, kidney and spleen of normal mice. Strong expression of MITF is noted in the heart. (D) Western blot analysis of H9C2 cardiomyocytes, MC-9 mast cells, B16 melanoma cells, rat basophilic leukemia (RBL) cells, and primary culture of rat neonatal cardiomyocytes (cardio). MITF appears in cardiomyocytes at approximately the same molecular weight as in mast cells but not in melanocytes. (E and F) Immunohistochemical staining of MITF using monoclonal antibody directed against the NH2 terminus in normal (E) and tg/tg mutated (F) hearts. MITF staining is absent in tg/tg mutated hearts. Scale bars: 100 μm. Higher magnification appears in the inset. (G) cDNA from hearts of either WT or tg/tg and ce/ce MITF-mutated mice and their normal littermates (sp/sp) were amplified by PCR. Four mouse MITF alternative first exons (1a, 1e, 1h, and 1m) were used as sense primers, and exon 5 was used as antisense. Numbers on the left indicate molecular weight (bp). (H) Schematic representation of splicing patterns described for MITF. Numbers on the left of slashes represent clones including exon 6a; numbers on the right represent clones without exon 6a. Most clones are full length, including exon 6a.
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