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. 2009 Apr 10;104(7):887-95.
doi: 10.1161/CIRCRESAHA.108.192328. Epub 2009 Feb 26.

Activation of the bone morphogenetic protein receptor by H11kinase/Hsp22 promotes cardiac cell growth and survival

Xiangzhen Sui  1 , Dan Li, Hongyu Qiu, Vinciane Gaussin, Christophe Depre
Affiliations

Activation of the bone morphogenetic protein receptor by H11kinase/Hsp22 promotes cardiac cell growth and survival

Xiangzhen Sui et al. Circ Res. .

Abstract

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 [(3)H]phenylalanine incorporation, and by a 70% reduction in H(2)O(2)-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-beta-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.

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