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(Circulation Research. 2009;104:887.)
© 2009 American Heart Association, Inc.

Cellular Biology

Activation of the Bone Morphogenetic Protein Receptor by H11Kinase/Hsp22 Promotes Cardiac Cell Growth and Survival

Xiangzhen Sui, Dan Li, Hongyu Qiu, Vinciane Gaussin, Christophe Depre

From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry New Jersey, New Jersey Medical School, Newark.

Correspondence to Christophe Depre, MD, PhD, Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 185 S Orange Ave, MSB G-609, Newark, NJ 07103. E-mail deprech{at}umdnj.edu

H11 kinase/Hsp22 (H11K) is a chaperone promoting cardiac cell growth and survival through the activation of Akt, a downstream effector of phosphatidylinositol 3-kinase (PI3K). In this study, we tested whether H11K-induced activation of the PI3K/Akt pathway is mediated by the bone morphogenetic protein (BMP) signaling, both in a transgenic mouse model with cardiac-specific overexpression of H11K and in isolated cardiac myocytes. Microarrays in hearts from transgenic compared to wild-type mice showed an upregulation of the BMP receptors Alk3 and BMPR-II, and of their ligand BMP4 (P<0.01 versus wild type). Activation of the BMP pathway in transgenic mice was confirmed by increased phosphorylation of the "canonical" BMP effectors Smad 1/5/8 (P<0.01 versus wild type). In isolated myocytes, adenovirus-mediated overexpression of H11K was accompanied by a significant (P<0.01) increase in PI3K activity, phospho-Akt, Smad 1/5/8 phosphorylation and [³H]phenylalanine incorporation, and by a 70% reduction in H₂O₂-mediated apoptosis. All these effects were abolished by the BMP antagonist noggin. In presence of BMP4, Smad 1/5/8 phosphorylation was enhanced by 5-fold on H11K overexpression but decreased by 3-fold on H11K knockdown (P<0.01 versus control), showing that H11K potentiates the BMP signaling. In pull-down experiments, H11K increased both the association of Alk3 and BMPR-II together, and their interaction with the transforming growth factor-β–activated kinase (TAK)1, a "noncanonical" mediator of the BMP receptor signaling. TAK1 inhibition prevented H11K-mediated activation of Akt. Therefore, potentiation of the BMP receptor by H11K promotes an activation of the PI3K/Akt pathway mediated by TAK1, which dictates the physiological effects of H11K on cardiac cell growth and survival.

Key Words: Akt • bone morphogenetic protein • heat shock protein • phosphatidylinositol 3-kinase

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