肌肉肥大
内科学
内分泌学
血管紧张素II
钙调神经磷酸酶
骨形态发生蛋白
SMAD公司
信号转导
骨形态发生蛋白2
蛋白激酶B
化学
生物
转化生长因子
细胞生物学
受体
医学
移植
基因
生物化学
体外
作者
Shahid Mohd,Ester Spagnolli,Laura Ernande,Robrecht Thoonen,Starsha Kolodziej,Patricio Leyton,Juan Cheng,Robert E. Tainsh,Claire Mayeur,David K. Rhee,Minxian Wu,Marielle Scherrer‐Crosbie,Emmanuel Buys,Warren M. Zapol,Kenneth D. Bloch,Donald B. Bloch
出处
期刊:American Journal of Physiology-heart and Circulatory Physiology
[American Physiological Society]
日期:2016-04-15
卷期号:310 (8): H984-H994
被引量:17
标识
DOI:10.1152/ajpheart.00879.2015
摘要
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.
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