Foxo transcription factors blunt cardiac hypertrophy by inhibiting calcineurin signaling

• Published in: Circulation (New York, N.Y.) Vol. 114; no. 11; pp. 1159 - 1168
• Main Authors: NI, Yan G, BERENJI, Kambeez, GERARD, Robert D, ROTHERMEL, Beverly A, HILL, Joseph A, NA WANG, OH, Misook, SACHAN, Nita, DEY, Asim, JUN CHENG, GUANGRONG LU, MORRIS, David J, CASTRILLON, Diego H
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 12.09.2006
• Subjects: Angiotensin II - pharmacology; Animals; Biological and medical sciences; Blood and lymphatic vessels; Calcineurin - physiology; Calcium-Binding Proteins; Cardiology. Vascular system; Cardiomegaly - genetics; Cardiomegaly - pathology; Cardiomegaly - physiopathology; Cells, Cultured; Coronary heart disease; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Forkhead Box Protein O1; Forkhead Box Protein O3; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene Expression Regulation - physiology; Heart; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Male; Medical sciences; Mice; Mice, Inbred C57BL; Muscle Proteins - genetics; Muscle Proteins - metabolism; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; NFATC Transcription Factors - genetics; NFATC Transcription Factors - metabolism; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphoric Monoester Hydrolases - drug effects; Phosphoric Monoester Hydrolases - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Sprague-Dawley; Signal Transduction - physiology; Transcription Factors - genetics; Transcription Factors - metabolism; Cardiovascular disease; Renin angiotensin system; Transcription factor; calcineurin; hypertrophy; Angiotensin
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circulationaha.106.637124

Cellular hypertrophy requires coordinated regulation of progrowth and antigrowth mechanisms. In cultured neonatal cardiomyocytes, Foxo transcription factors trigger an atrophy-related gene program that counters hypertrophic growth. However, downstream molecular events are not yet well defined. Here, we report that expression of either Foxo1 or Foxo3 in cardiomyocytes attenuates calcineurin phosphatase activity and inhibits agonist-induced hypertrophic growth. Consistent with these results, Foxo proteins decrease calcineurin phosphatase activity and repress both basal and hypertrophic agonist-induced expression of MCIP1.4, a direct downstream target of the calcineurin/NFAT pathway. Furthermore, hearts from Foxo3-null mice exhibit increased MCIP1.4 abundance and a hypertrophic phenotype with normal systolic function at baseline. Together, these results suggest that Foxo proteins repress cardiac growth at least in part through inhibition of the calcineurin/NFAT pathway. Given that hypertrophic growth of the heart occurs in multiple contexts, our findings also suggest that certain hypertrophic signals are capable of overriding the antigrowth program induced by Foxo. Consistent with this, multiple hypertrophic agonists triggered inactivation of Foxo proteins in cardiomyocytes through a mechanism requiring the PI3K/Akt pathway. In addition, both Foxo1 and Foxo3 are phosphorylated and consequently inactivated in hearts undergoing hypertrophic growth induced by hemodynamic stress. This study suggests that inhibition of the calcineurin/NFAT signaling cascade by Foxo and release of this repressive action by the PI3K/Akt pathway are important mechanisms whereby Foxo factors govern cell growth in the heart.