Transcription factor MITF regulates cardiac growth and hypertrophy

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.

Identificación y expresión diferencial del factor de transcripción asociado a microftalmia en corazón y cardiomiocitos aislados de cobayo, posible papel en hipertrofia y en viabilidad

“…Los análisis de expresión del MITF-H empleando los ADNc obtenidos de células sometidas a lesión por isquemia simulada, muestran que la expresión del ARNm del MITF-H disminuye con respecto al grupo de células sometidas a protección por preacondicionamiento isquémico (figura 6), lo que indica que el MITF puede estar implicado en la regulación de la viabilidad en respuesta a la isquemia inducida experimentalmente. Este resultado permite sugerir que, en el caso del modelo presentado en este trabajo, la hipertrofia se podría presentar asociada a una respuesta adaptativa alterada como consecuencia de la pérdida del número de cardiomiocitos y de la masa contráctil del miocardio, mientras que, en el caso de la hipertrofia cardiaca en el modelo de ratón (32), ésta podría estar asociada a una respuesta adaptativa alterada frente a la presión arterial inducida.…”

“…Se ha propuesto recientemente la existencia de una relación entre el MITF y el crecimiento y la hipertrofia cardiaca (32,33). En este sentido, Tshori, et al, reportaron que los ratones con mutación en el gen del MITF mostraban una disminución en la respuesta hipertrófica ante la estimulación beta-adrenérgica, así como una disminución en la función cardiaca y tendencia a la muerte súbita, y concluyeron que el MITF puede jugar un papel importante en la hipertrofia cardiaca inducida por beta-adrenérgicos.…”

FHL2 switches MITF from activator to repressor of Erbin expression during cardiac hypertrophy

“…We have previously demonstrated that the H isoform of MITF is highly expressed in cardiomyocytes [7], and that MITF-mutated mice have a diminished cardiac hypertrophic response to β-adrenergic stimulation, decreased cardiac function and a tendency for sudden death [8]. Moreover, we reported that middle-aged MITF-mutated mice have a much smaller heart mass and decreased cardiac function and output [8].…”

“…Moreover, we reported that middle-aged MITF-mutated mice have a much smaller heart mass and decreased cardiac function and output [8]. These observations indicate that MITF plays an essential role in the development of cardiac hypertrophy [8].…”

“…Moreover, we reported that middle-aged MITF-mutated mice have a much smaller heart mass and decreased cardiac function and output [8]. These observations indicate that MITF plays an essential role in the development of cardiac hypertrophy [8]. In order to identify cardiac MITF target genes, we conducted a gene array analysis of mRNA from a pool of hearts derived from middle-aged MITF mutated mice ( ce/ce ) and compared it to that from normal siblings ( sp/sp ).…”