J Clin Invest. 2014 Aug;124(8):3514-28. doi: 10.1172/JCI74773.

Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension.

Bertero T, Lu Y, Annis S, Hale A, Bhat B, Saggar R, Saggar R, Wallace WD, Ross DJ, Vargas SO, Graham BB, Kumar R, Black SM, Fratz S, Fineman JR, West JD, Haley KJ, Waxman AB, Chau BN, Cottrill KA, Chan SY.

 

Abstract

Development of the vascular disease pulmonary hypertension (PH) involves disparate molecular pathways that span multiple cell types. MicroRNAs (miRNAs) may coordinately regulate PH progression, but the integrative functions of miRNAs in this process have been challenging to define with conventional approaches. Here, analysis of the molecular network architecture specific to PH predicted that the miR-130/301 family is a master regulator of cellular proliferation in PH via regulation of subordinate miRNA pathways with unexpected connections to one another. In validation of this model, diseased pulmonary vessels and plasma from mammalian models and human PH subjects exhibited upregulation of miR-130/301 expression. Evaluation of pulmonary arterial endothelial cells and smooth muscle cells revealed that miR-130/301 targeted PPARγ with distinct consequences. In endothelial cells, miR-130/301 modulated apelin-miR-424/503-FGF2 signaling, while in smooth muscle cells, miR-130/301 modulated STAT3-miR-204 signaling to promote PH-associated phenotypes. In murine models, induction of miR-130/301 promoted pathogenic PH-associated effects, while miR-130/301 inhibition prevented PH pathogenesis. Together, these results provide insight into the systems-level regulation of miRNA-disease gene networks in PH with broad implications for miRNA-based therapeutics in this disease. Furthermore, these findings provide critical validation for the evolving application of network theory to the discovery of the miRNA-based origins of PH and other diseases.

PMID: 24960162

 

Supplement

Pulmonary hypertension is a deadly vascular disease with undefined origins. It occurs when there is increased pressure in the blood vessels of the lung, thus compromising the delivery of blood and oxygen to the body. Symptoms are debilitating and include shortness of breath and fatigue but can progress to heart failure and death.

Despite the rising number of people diagnosed with this disease worldwide, pulmonary hypertension has been a historically neglected disease. Furthermore, it is an example of a cardiovascular disease so complex that traditional methods of research have failed to provide adequate treatments to prevent or halt its progression. Our laboratory has been advancing the idea that mathematical models of this disease can be generated to perform high-volume, systematic analyses that are not feasible with standard experimentation. In doing so, we can make predictions regarding critical molecular networks that underlie the molecular origins of pulmonary hypertension that have not been possible to this point.

In this study (1), we focused on the biology of microRNAs, which are small, non-coding nucleic acid molecules that can block production of numerous proteins in human cells with implications in health and disease. With the help of novel computational analyses, we developed a unique molecular model tracing the architecture interconnecting the network of genes and microRNAs associated with pulmonary hypertension.

Historically, most computational approaches in the study of human disease gene networks go no further than theoretical predictions. We wanted to be sure that our predictions were truly valid in real instances of pulmonary hypertension. Consequently, we confirmed our mathematical predictions with experiments using a wide range of pre-clinical and human models. In doing so, we identified the microRNA family, miR-130/301, as a master regulator of diverse target genes and additional microRNAs, ultimately orchestrating a global proliferative response in diseased blood vessels leading to pulmonary hypertension.

This is the first microRNA family found to regulate such a diverse number of pathways specific for pulmonary hypertension. Consequently, these molecules could be very effective therapeutic targets for treating this deadly disease. Moreover, this is one of the first studies to leverage successfully advanced computational network modeling to decipher the molecular secrets of such a complex human disease. Thus, since all of these findings were previously missed by conventional experiments, our efforts provide great support for using network modeling to discover the molecular origins of diseases beyond the pulmonary vascular bed.

 

fig1References

  1. Bertero T, Lu Y, Annis S, Hale A, Bhat B, Saggar R, Saggar R, Wallace WD, Ross DJ, Vargas SO, Graham BB, Kumar R, Black SM, Fratz S, Fineman JR, West JD, Haley KJ, Waxman AB, Chau BN, Cottrill KA, Chan SY. Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension. The Journal of Clinical Investigation. 2014; 124(8):3514-3528. (Recommended in F1000Prime as being of special significance in its field).

Acknowledgments

This research was supported by the National Institutes of Health (K08HL096834, HL67841, HL61284); the McArthur-Radovsky, Lerner, Harris, and Watkins Funds; and the Pulmonary Hypertension Association.

 

Corresponding author

Stephen Y. Chan, MD, PhD, FAHA Assistant Professor of Medicine, Harvard Medical School Associate Physician, Brigham and Women’s Hospital 77 Avenue Louis Pasteur, Room 630N Boston, MA, USA 02115 Tel: 617-525-4844 Fax: 617-525-4830 Email: sychan@partners.org URL: www.sychanlab.net

 

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