Pulmonary hypertension (PH) is a deadly vascular disease linked to an enigmatic repression of mitochondrial metabolism. Iron-sulfur (Fe-S) clusters are prosthetic groups that promote mitochondrial respiration and are regulated by the Fe-S assembly proteins ISCU and FXN (frataxin). Yet, the roles of Fe-S clusters in most human diseases including PH are unknown. We found that hypoxia-induced microRNA-210 represses ISCU, promoting Fe-S deficiency, pulmonary vascular metabolic dysregulation, and PH. We also found that FXN is down-regulated in PH and is controlled by the miR-130/301 family/PPAR? regulatory axis. We hypothesize that Fe-S deficiency, particularly in pulmonary vascular endothelium, is a critical pathogenic lynchpin of PH and is a common convergence point of genetic and acquired disease triggers. We plan to study both rodents and humans in vivo, delineating novel Fe-S-based origins of PH - namely, the coordinated microRNA-based regulation of ISCU/FXN by hypoxia and human genetic deficiencies of ISCU and FXN.
Specific Aims : 1) Determine whether the miR-130/301 family represses FXN and Fe-S expression in order to control PH. In a hypoxic mouse model of PH and cultured pulmonary vascular endothelial cells from diseased mice coupled with novel biophysical assays to measure Fe-S levels, we will test the hypothesis that the miR-130/301 family down-regulates FXN in order to repress Fe-S biogenesis and mitochondrial respiration and thus promote PH. Such findings would identify miR-130/301-dependent control of FXN as a critical complement to the miR-210/ISCU axis in metabolic dysfunction and in the overall control of PH. 2) Determine whether up-regulation of miR-210 and miR-130/301 together promotes more robust down- regulation of Fe-S cluster expression and more severe PH manifestation than either miRNA alone. Using the model systems above, we will test the hypothesis that up-regulation of miR-210 and miR-130/301 together promote more robust down-regulation of Fe-S integrity and increased PH severity. Results would be invaluable for developing a roadmap for synergistic therapeutic targeting of microRNAs in PH. 3) Determine whether mutations of ISCU and FXN in humans directly promote PH. To assess for PH in human genetic deficiency of FXN or ISCU without hypoxia, we plan advanced cardiopulmonary exercise tests. We will also generate/study patient-specific inducible pluripotent stem cells to determine how the mutations control pulmonary vascular function. This rare combination of molecular study and patient testing should define PH risk in Fe-S deficiency, guiding clinical care and solidifying this paradigm's relevance in humans. Significance: This proposal incorporates rigorous expertise and new technological advancements in Fe-S biology coupled with a rare opportunity to translate mechanistic findings directly to humans.
We aim to firmly establish Fe-S deficiency as a powerful and novel metabolic disease origin, a new therapeutic target for PH, and a foundation for discovery in other diseases that share similar hypoxic and metabolic underpinnings.

Public Health Relevance

In this proposal, we aim to firmly establish the novel paradigm of pulmonary hypertension driven primarily by a deficiency of iron-sulfur clusters -- essential bioinorganic factors that have been poorly studied in human disease. If successful, we hope to prove this mechanism as an elusive upstream disease origin in a number of undiagnosed individuals at risk for pulmonary hypertension and that synergistic therapeutic targeting of this pathway may prevent or even reverse this devastating disease. Furthermore, as exceedingly little is known about the regulation and function of iron-sulfur clusters in chronic acquired human diseases, the results could define an entirely novel disease origin applicable to conditions other than PH that share similar hypoxic-ischemic and metabolic pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL122596-04
Application #
9252504
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Xiao, Lei
Project Start
2015-09-01
Project End
2020-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
4
Fiscal Year
2017
Total Cost
$387,419
Indirect Cost
$118,519
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Masri, Ahmad; Abdelkarim, Islam; Sharbaugh, Michael S et al. (2018) Outcomes of persistent pulmonary hypertension following transcatheter aortic valve replacement. Heart 104:821-827
Sun, Wei; Chan, Stephen Y (2018) Pulmonary Arterial Stiffness: An Early and Pervasive Driver of Pulmonary Arterial Hypertension. Front Med (Lausanne) 5:204
Florentin, Jonathan; Coppin, Emilie; Vasamsetti, Sathish Babu et al. (2018) Inflammatory Macrophage Expansion in Pulmonary Hypertension Depends upon Mobilization of Blood-Borne Monocytes. J Immunol 200:3612-3625
Han, Yuchi; Forfia, Paul R; Vaidya, Anjali et al. (2018) Rationale and design of the ranolazine PH-RV study: a multicentred randomised and placebo-controlled study of ranolazine to improve RV function in patients with non-group 2 pulmonary hypertension. Open Heart 5:e000736
Brittain, Evan L; Thennapan, Thennapan; Maron, Bradley A et al. (2018) Update in Pulmonary Vascular Disease 2016 and 2017. Am J Respir Crit Care Med 198:13-23
Bertero, Thomas; Oldham, William M; Grasset, Eloise M et al. (2018) Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy. Cell Metab :
Yu, Qiujun; Chan, Stephen Y (2017) Mitochondrial and Metabolic Drivers of Pulmonary Vascular Endothelial Dysfunction in Pulmonary Hypertension. Adv Exp Med Biol 967:373-383
Lam, Hilaire C; Baglini, Christian V; Lope, Alicia Llorente et al. (2017) p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis. Cancer Res 77:3255-3267
Negi, Vinny; Chan, Stephen Y (2017) Discerning functional hierarchies of microRNAs in pulmonary hypertension. JCI Insight 2:e91327
Cavalcante, João L; Simon, Marc A; Chan, Stephen Y (2017) Comprehensive Right-Sided Assessment for Transcatheter Aortic Valve Replacement Risk Stratification: Time for a Change. J Am Soc Echocardiogr 30:47-51

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