Pulmonary arterial hypertension (PAH) is characterized by an increase in pulmonary vascular resistance that impedes ejection of blood by the right ventricle, leading to right ventricular failure. PAH is a serious condition for which there is no cure. Primary PAH is a rare but progressive disease with a mortality of 30 percent over 4 years. Recently germline mutations in bone morphogenetic protein receptor type II (BMPRII), a member of the transforming growth factor 2 (TGF2) receptor family, have been found in over 80 percent of familial PAH patients and in 30 percent of sporadic cases of PAH. The long-term objective of this application is to understand the molecular mechanism(s) by which BMPRII mutations contribute to the pathogenesis of PAH. The hypothesis of this application is that BMPR2 and its downstream signal are essential for maintenance of a normal pulmonary vascular structure and function. We have shown previously that the TGF2 family of growth factors, TGF2s and BMPs, promote a switch from a """"""""synthetic"""""""" to """"""""contractile"""""""" phenotype of pulmonary artery smooth muscle cells (PASMCs) by inducing the expression of VSMC-specific genes. We recently demonstrated that the expression of microRNA-21 (miR-21) is rapidly induced after a treatment with TGF2 or BMP in PASMCs. MiR-21 belongs to a family of short, noncoding, single-stranded RNAs (ssRNAs) called microRNAs (miRNAs) that regulate gene expression by targeting mRNAs in a sequence-specific manner, causing translational repression or mRNA degradation. Induction of miR-21 in PASMCs leads to downregulation of Programmed Cell Death 4 (PDCD4) which in turn leads to the elevation of VSMC-specific gene expression. Interestingly, our data indicate that TGF2 and BMP mediate miR-21 induction post- transcriptionally by promoting the processing of primary transcripts of miR-21 (pri-miR-21) into precursor miR- 21 (pre-miR-21) by the Drosha microprocessor complex in the nucleus. The main goal of this application is to investigate a mechanism of regulation of miR-21 biosynthesis by TGF2 and BMP, which is crucial for understanding a molecular mechanism of TGF2/BMP-mediated phenotype switch underlying the pathogenesis of PAH. To this end, SA1 will examine a mechanism of association of Smads with specific pri-miRNAs. SA2 will elucidate a role of Smad proteins in the TGF2/BMP-regulated pri-miR-21 processing. SA3 will explore a role of miR-21 target PDCD4 in the regulation of vascular smooth muscle phenotype. This application investigates the previously unexplored mechanism of gene regulation by the TGF2/BMP-Smad signaling pathway which is fundamental for understanding the pathogenesis and development of novel therapies for PAH.

Public Health Relevance

Vascular smooth muscle cells (VSMC) are characterized in part by their ability to modulate their phenotype between a quiescent, differentiated """"""""contractile"""""""" state and a proliferative, less differentiated, """"""""synthetic"""""""" state;further, upon vascular damage, VSMCs adopt the synthetic phenotype as part of a normal repair process. It is suggested that the phenotypic modulation of VSMCs contributes to various disorders in the pulmonary and systemic arteries, including post-angioplasty re-stenosis, transplant vasculopathy, atherosclerosis, lymphangioleiomyomatosis, and pulmonary arterial hypertension (PAH). This application will elucidate a novel mechanism of regulation of VSMC phenotype in normal physiology, which is of fundamental importance in understanding the etiology of cardiovascular disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL093154-05
Application #
8266380
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Reid, Diane M
Project Start
2009-06-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$382,388
Indirect Cost
$134,888
Name
University of California San Francisco
Department
Biochemistry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Kang, Hara; Hata, Akiko (2016) Quantitative Real-Time PCR Analysis of MicroRNAs and Their Precursors Regulated by TGF-β Signaling. Methods Mol Biol 1344:313-23
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
Sessa, Roberto; Hata, Akiko (2013) Role of microRNAs in lung development and pulmonary diseases. Pulm Circ 3:315-28
Blahna, Matthew T; Hata, Akiko (2013) Regulation of miRNA biogenesis as an integrated component of growth factor signaling. Curr Opin Cell Biol 25:233-40
Kang, Hara; Louie, Justin; Weisman, Alexandra et al. (2012) Inhibition of microRNA-302 (miR-302) by bone morphogenetic protein 4 (BMP4) facilitates the BMP signaling pathway. J Biol Chem 287:38656-64
Kang, Hara; Davis-Dusenbery, Brandi N; Nguyen, Peter H et al. (2012) Bone morphogenetic protein 4 promotes vascular smooth muscle contractility by activating microRNA-21 (miR-21), which down-regulates expression of family of dedicator of cytokinesis (DOCK) proteins. J Biol Chem 287:3976-86
McDonald, Robert A; Hata, Akiko; MacLean, Margaret R et al. (2012) MicroRNA and vascular remodelling in acute vascular injury and pulmonary vascular remodelling. Cardiovasc Res 93:594-604

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