BMP type I receptor ALK2 is required for angiotensin II-induced cardiac hypertrophy.

American journal of physiology. Heart and circulatory physiology 2016 Apr 15

filter terms:

Bone morphogenetic protein (BMP) signaling contributes to the development of cardiac hypertrophy. However, the identity of the BMP type I receptor involved in cardiac hypertrophy and the underlying molecular mechanisms are poorly understood. By using quantitative PCR and immunoblotting, we demonstrated that BMP signaling increased during phenylephrine-induced hypertrophy in cultured neonatal rat cardiomyocytes (NRCs), as evidenced by increased phosphorylation of Smads 1 and 5 and induction of Id1 gene expression. Inhibition of BMP signaling with LDN193189 or noggin, and silencing of Smad 1 or 4 using small interfering RNA diminished the ability of phenylephrine to induce hypertrophy in NRCs. Conversely, activation of BMP signaling with BMP2 or BMP4 induced hypertrophy in NRCs. Luciferase reporter assay further showed that BMP2 or BMP4 treatment of NRCs repressed atrogin-1 gene expression concomitant with an increase in calcineurin protein levels and enhanced activity of nuclear factor of activated T cells, providing a mechanism by which BMP signaling contributes to cardiac hypertrophy. In a model of cardiac hypertrophy, C57BL/6 mice treated with angiotensin II (A2) had increased BMP signaling in the left ventricle. Treatment with LDN193189 attenuated A2-induced cardiac hypertrophy and collagen deposition in left ventricles. Cardiomyocyte-specific deletion of BMP type I receptor ALK2 (activin-like kinase 2), but not ALK1 or ALK3, inhibited BMP signaling and mitigated A2-induced cardiac hypertrophy and left ventricular fibrosis in mice. The results suggest that BMP signaling upregulates the calcineurin/nuclear factor of activated T cell pathway via BMP type I receptor ALK2, contributing to cardiac hypertrophy and fibrosis. Copyright © 2016 the American Physiological Society.

Citation

Mohd Shahid, Ester Spagnolli, Laura Ernande, Robrecht Thoonen, Starsha A Kolodziej, Patricio A Leyton, Juan Cheng, Robert E T Tainsh, Claire Mayeur, David K Rhee, Mei X Wu, Marielle Scherrer-Crosbie, Emmanuel S Buys, Warren M Zapol, Kenneth D Bloch, Donald B Bloch. BMP type I receptor ALK2 is required for angiotensin II-induced cardiac hypertrophy. American journal of physiology. Heart and circulatory physiology. 2016 Apr 15;310(8):H984-94