Idiopathic pulmonary arterial hypertension (IPAH) is a rare but terminal disease with a median survival rate of 2-3 years from the time of diagnosis if left untreated. Bone morphogenetic proteins (BMPs), the largest subset in the transforming growth factor 2 (TGF2) superfamily of cytokines, play a crucial role in such fundamental processes as dorso-ventral patterning, left-right asymmetry, neurogenesis, somite and skeletal development, limb patterning, and organogenesis. Germline mutations of the type II BMP receptor (BMPRII) genes are associated with IPAH. Mutations causing IPAH are distributed throughout the BMPRII gene, including the carboxyl (C)-terminal tail domain [BMPRII(TD)], which has no catalytic activity. There is a critical need to understand how mutations in BMPRII, and in particular in the poorly characterized BMPRII(TD), contribute to the pathogenesis of IPAH, so that an effective and rational therapy may be devised. The long-term objective of this proposal is to elucidate the mechanism by which BMPRII(TD) transmits a specific signal, in order to gain further insights into the molecular pathogenesis of IPAH. We discovered that four-and-a-half LIM-domains 2 (FHL2) interacts with the wild type BMPRII(TD) but not with the C-terminal deletion mutant of BMPRII(TD) identified in IPAH. The central hypothesis of the application is that FHL2, through its interaction with BMPRII(TD), plays a critical role in the maintenance of normal vascular tone. Upon BMP4 stimulation, FHL2 translocates to the nucleus and inhibits BMP-mediated activation of vascular smooth muscle cell (VSMC)- specific contractile genes in pulmonary artery smooth muscle cells (PASMCs). VSMC-specific gene promoters are regulated by a complex of proteins composed of serum response factor (SRF) and coactivators, such as MRTFs (MRTF-A or MRTF-B), and chromatin remodeling factor Brg1, which binds to a DNA element named 'CArG box'. Our results indicate that FHL2 disrupts BMP-mediated recruitment of Brg1 to VSMC-specific gene promoters, thereby resulting in inhibition of recruitment of RNA polymerase II (Pol II) and transcription. Preliminary studies of FHL2 homozygous-null [FHL2(KO)] mice revealed the exciting finding that these mice are hypertensive and exhibit abnormality in the vascular tone of large blood vessels. In SA1, we will elucidate the molecular mechanism by which the BMPRII(TD)-FHL2 pathway modulates VSMC gene transcription. In SA2, we will clarify the role of the BMPRII(TD)-FHL2-mediated signal in VSMC phenotype control. In SA3, we will investigate the role of BMPRII(TD)-FHL2 in vascular remodeling and vascular homeostasis. Successful completion of these aims is expected to provide insight into the etiology of IPAH and new targets for preventive or therapeutic interventions of vascular proliferative diseases, such as IPAH, restenosis, and atherosclerosis.
Idiopathic pulmonary arterial hypertension (IPAH) has a mean age at diagnosis of 36 years; and is usually fatal within 3 years if untreated. Germline mutations of the type II BMP receptor (BMPRII) gene are associated with IPAH. By studying a protein called FHL2 that interacts with BMPRII and regulates BMPRII function; this application will investigate the etiology of IPAH.
|Kashima, Risa; Redmond, Patrick L; Ghatpande, Prajakta et al. (2017) Hyperactive locomotion in a Drosophila model is a functional readout for the synaptic abnormalities underlying fragile X syndrome. Sci Signal 10:|
|Jiang, Xuan; Hawkins, John S; Lee, Jerry et al. (2017) Let-7 microRNA-dependent control of leukotriene signaling regulates the transition of hematopoietic niche in mice. Nat Commun 8:128|
|Kashima, Risa; Roy, Sougata; Ascano, Manuel et al. (2016) Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome. Sci Signal 9:ra58|
|Kang, Hara; Hata, Akiko (2016) Quantitative Real-Time PCR Analysis of MicroRNAs and Their Precursors Regulated by TGF-? Signaling. Methods Mol Biol 1344:313-23|
|Hata, Akiko; Kashima, Risa (2016) Dysregulation of microRNA biogenesis machinery in cancer. Crit Rev Biochem Mol Biol 51:121-34|
|Nazer, Babak; Gerstenfeld, Edward P; Hata, Akiko et al. (2014) Cardiovascular applications of therapeutic ultrasound. J Interv Card Electrophysiol 39:287-94|
|Kim, Sunghwan; Hata, Akiko; Kang, Hara (2014) Down-regulation of miR-96 by bone morphogenetic protein signaling is critical for vascular smooth muscle cell phenotype modulation. J Cell Biochem 115:889-95|
|Chang, Jonathan; Davis-Dusenbery, Brandi N; Kashima, Risa et al. (2013) Acetylation of p53 stimulates miRNA processing and determines cell survival following genotoxic stress. EMBO J 32:3192-205|
|Hata, Akiko (2013) Functions of microRNAs in cardiovascular biology and disease. Annu Rev Physiol 75:69-93|
|Arora, Pankaj; Wu, Connie; Khan, Abigail May et al. (2013) Atrial natriuretic peptide is negatively regulated by microRNA-425. J Clin Invest 123:3378-82|
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