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1.
Am J Physiol Heart Circ Physiol ; 310(8): H984-94, 2016 Apr 15.
Article in English | MEDLINE | ID: mdl-26873969

ABSTRACT

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.


Subject(s)
Activin Receptors, Type I/metabolism , Angiotensin II , Bone Morphogenetic Protein 2/pharmacology , Bone Morphogenetic Protein 4/pharmacology , Bone Morphogenetic Protein Receptors, Type I/metabolism , Cardiomegaly/enzymology , Myocytes, Cardiac/enzymology , Activin Receptors, Type I/deficiency , Activin Receptors, Type I/genetics , Activin Receptors, Type II , Animals , Bone Morphogenetic Protein Receptors, Type I/deficiency , Bone Morphogenetic Protein Receptors, Type I/genetics , Cardiomegaly/chemically induced , Cardiomegaly/genetics , Cardiomegaly/pathology , Cardiomegaly/prevention & control , Cells, Cultured , Disease Models, Animal , Dose-Response Relationship, Drug , Fibrosis , Inhibitor of Differentiation Protein 1/genetics , Inhibitor of Differentiation Protein 1/metabolism , Mice, Inbred C57BL , Mice, Knockout , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/pathology , NFATC Transcription Factors/metabolism , Phenylephrine/pharmacology , Phosphorylation , Pyrazoles/pharmacology , Pyrimidines/pharmacology , RNA Interference , Rats, Sprague-Dawley , Signal Transduction , Smad Proteins/genetics , Smad Proteins/metabolism , Time Factors , Transfection
2.
Blood ; 124(13): 2116-23, 2014 Sep 25.
Article in English | MEDLINE | ID: mdl-25075125

ABSTRACT

Expression of hepcidin, the hepatic hormone controlling iron homeostasis, is regulated by bone morphogenetic protein (BMP) signaling. We sought to identify which BMP type II receptor expressed in hepatocytes, ActR2a or BMPR2, is responsible for regulating hepcidin gene expression. We studied Bmpr2 heterozygous mice (Bmpr2(+/-)), mice with hepatocyte-specific deficiency of BMPR2, mice with global deficiency of ActR2a, and mice in which hepatocytes lacked both BMPR2 and ActR2a. Hepatic hepcidin messenger RNA (mRNA) levels, serum hepcidin and iron levels, and tissue iron levels did not differ in wild-type mice, Bmpr2(+/-) mice, and mice in which either BMPR2 or ActR2a was deficient. Deficiency of both BMP type II receptors markedly reduced hepatic hepcidin gene expression and serum hepcidin levels leading to severe iron overload. Iron injection increased hepatic hepcidin mRNA levels in mice deficient in either BMPR2 or ActR2a, but not in mice deficient in both BMP type II receptors. In addition, in mouse and human primary hepatocytes, deficiency of both BMPR2 and ActR2a profoundly decreased basal and BMP6-induced hepcidin gene expression. These results suggest that BMP type II receptors, BMPR2 and ActR2a, have redundant roles in the regulation of hepatic hepcidin gene expression and iron metabolism.


Subject(s)
Bone Morphogenetic Protein Receptors, Type II/metabolism , Gene Expression Regulation , Hepatocytes/metabolism , Hepcidins/genetics , Iron/metabolism , Actin-Related Protein 2/deficiency , Animals , Bone Morphogenetic Protein Receptors, Type II/deficiency , Bone Morphogenetic Protein Receptors, Type II/genetics , Female , Gene Deletion , Heterozygote , Humans , Iron Overload/genetics , Iron Overload/metabolism , Liver/metabolism , Liver/pathology , Mice , Mice, Knockout , Mutation , RNA, Messenger/genetics , Signal Transduction
3.
PLoS One ; 8(10): e76947, 2013.
Article in English | MEDLINE | ID: mdl-24116187

ABSTRACT

The bone morphogenetic protein (BMP) type II receptor (BMPR2) has a long cytoplasmic tail domain whose function is incompletely elucidated. Mutations in the tail domain of BMPR2 are found in familial cases of pulmonary arterial hypertension. To investigate the role of the tail domain of BMPR2 in BMP signaling, we generated a mouse carrying a Bmpr2 allele encoding a non-sense mediated decay-resistant mutant receptor lacking the tail domain of Bmpr2. We found that homozygous mutant mice died during gastrulation, whereas heterozygous mice grew normally without developing pulmonary arterial hypertension. Using pulmonary artery smooth muscle cells (PaSMC) from heterozygous mice, we determined that the mutant receptor was expressed and retained its ability to transduce BMP signaling. Heterozygous PaSMCs exhibited a BMP7­specific gain of function, which was transduced via the mutant receptor. Using siRNA knockdown and cells from conditional knockout mice to selectively deplete BMP receptors, we observed that the tail domain of Bmpr2 inhibits Alk2­mediated BMP7 signaling. These findings suggest that the tail domain of Bmpr2 is essential for normal embryogenesis and inhibits Alk2­mediated BMP7 signaling in PaSMCs.


Subject(s)
Bone Morphogenetic Protein 7/pharmacology , Bone Morphogenetic Protein Receptors, Type II/genetics , Sequence Deletion , Activin Receptors, Type I/genetics , Activin Receptors, Type I/metabolism , Activin Receptors, Type II/genetics , Activin Receptors, Type II/metabolism , Animals , Binding Sites/genetics , Bone Morphogenetic Protein 4/pharmacology , Bone Morphogenetic Protein Receptors, Type II/metabolism , Cells, Cultured , Familial Primary Pulmonary Hypertension , Gene Expression/drug effects , Genotype , Hypertension, Pulmonary/genetics , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/physiopathology , Immunoblotting , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Confocal , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/metabolism , Pulmonary Artery/cytology , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , Smad6 Protein/genetics , Smad6 Protein/metabolism
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