1. STEPHEN Y. CHAN, Ying-Yi Zhang, Craig Hemann, Christopher E. Mahoney, Jay L. Zweier, Joseph Loscalzo. MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metabolism. 2009; 10 (4); 273 – 284.

Repression of mitochondrial respiration represents an evolutionarily ancient cellular adaptation to hypoxia, but its underlying molecular mechanisms are incompletely understood. This study identified the hypoxia-induced microRNA-210 as an essential regulator of the metabolic processes that govern this “Pasteur effect,” via repression of its direct target, the iron-sulfur cluster assembly proteins ISCU1/2 thus leading to a metabolic shift from mitochondrial oxidative phosphorylation to glycolysis. Taken together, these results identified important mechanistic connections among microRNAs, iron-sulfur cluster biology, hypoxia, and mitochondrial function, with broad implications for cellular metabolism and adaptation to stress.

2.  Aaron L. Baggish, Andrew Hale, Rory B. Weiner, Gregory D. Lewis, David Systrom, Francis Wang, Thomas J. Wang, STEPHEN Y. CHAN. Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training. Journal of Physiology. 589:3983-3994 (2011).

3.  Victoria N. Parikh, Richard C. Jin, Sabrina Rabello, Natali Gulbahce, Kevin White, Andrew Hale, Katherine A. Cottrill, Rahamthulla S. Shaik, Aaron B. Waxman, Ying-Yi Zhang, Bradley A. Maron, Jochen C. Hartner, Yuko Fujiwara, Stuart H. Orkin, Kathleen J. Haley, Albert-László Barabási, Joseph Loscalzo, STEPHEN Y. CHAN. MicroRNA-21 integrates pathogenic signaling to control pulmonary hypertension: results of a network bioinformatics approach. Circulation. 125:1520-1532 (2012).

A unique network biology–based approach was coupled with experimental validation in vitro and in vivo to identify microRNA-21 (miR-21) as a crucial pathogenic regulator in pulmonary hypertension (PH). This study was the first to demonstrate the utility of a network-based method for identifying disease modifying miRNAs.

4.  Jonathan W. Snow, Andrew Hale, Stephanie K. Isaacs, Aaron L. Baggish, STEPHEN Y. CHAN. Ineffective delivery of diet-derived microRNAs to recipient animal organisms. RNA Biology. 10: 1107-1116 (2013).

5.  Aaron L. Baggish, Joseph Park, Pil-Ki Min, Stephanie K. Isaacs, Beth A. Parker, Paul D. Thompson, Christopher Troyanos, Pierre D’Hemecourt, Sophia Dyer, Marissa Thiel, Andrew Hale, STEPHEN Y. CHAN. Rapid up-regulation and clearance of distinct circulating microRNAs after prolonged aerobic exercise. Journal of Applied Physiology. 116: 522-531 (2014).

6.  Thomas Bertero, Yu Lu, Sofia Annis, Andrew Hale, Balkrishen Bhat, Rajan Saggar, Rajeev Saggar, W. Dean Wallace, David J. Ross, Sara O. Vargas, Brian B. Graham, Rahul Kumar, Stephen M. Black, Sohrab Fratz, Jeffrey R. Fineman, James D. West, Kathleen J. Haley, Aaron B. Waxman, B. Nelson Chau, Katherine A. Cottrill, STEPHEN Y. CHAN. Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension. The Journal of Clinical Investigation. 124:3514-3528 (2014).

Guided by in silico network analysis and in vivo experimentation, this was the first description of any microRNA family, miR-130/301, regulating a hierarchy of subordinate microRNAs with global yet cell type-specific effects in PH. It defined the systems-level regulation of microRNA/gene networks in PH with broad implications on microRNA-based therapeutics.

7.  Andrew Hale, Changjin Lee, Sofia Annis, Pil-Ki Min, Reena Pande, Mark A. Creager, Colleen G. Julian, Lorna G. Moore, S. Alex Mitsialis, Sarah J. Hwang, Stella Kourembanas, STEPHEN Y. CHAN. An Argonaute 2 switch regulates circulating miR-210 to coordinate hypoxic adaptation across cells. Biochim Biophys Acta Molecular Cell Research. 1843:2528-2542 (2014).

8.  Thomas Bertero, Katherine Cottrill, Adrienn Krauszman, Yu Lu, Sofia Annis, Andrew Hale, Balkrishen Bhat, Aaron B. Waxman, B. Nelson Chau, Wolfgang M. Kuebler, STEPHEN Y. CHAN. The microRNA-130/301 family controls vasoconstriction in pulmonary hypertension. Journal of Biological Chemistry. 290:2069-2085 (2015).

9.  Kevin White, Yu Lu, Sofia Annis, Andrew E. Hale, B. Nelson Chau, James E. Dahlman, Craig Hemann, Alexander Opotowsky, Sara O. Vargas, Rosas I, Mark A. Perrella, Juan C. Osorio, Kathleen J. Haley, Brian B. Graham, Rahul Kumar, Rajan Saggar, Rajeev Saggar, W. Dean Wallace, David J. Ross, Omar F. Khan, Andrew Bader, Bernadette R. Gochuico, Majed Matar, Kevin Polach, Nicolai M. Johannessen, Daniel G. Anderson, Robert Langer, Jay L. Zweier, Laurence A. Bindoff, David Systrom, Aaron B. Waxman, Richard C. Jin, STEPHEN Y. CHAN. Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension. EMBO Molecular Medicine. 7:695-713 (2015).

This study identified the miR-210-ISCU1/2 axis as a pathogenic lynchpin causing iron-sulfur (Fe-S) deficiency and pulmonary hypertension (PH). It was first to report pulmonary vascular dysfunction in ISCU-deficient individuals. These findings have spurred development of diagnostics and therapeutics targeting Fe-S biogenesis in PH and diseases that share similar metabolic underpinnings.

10.  Victoria Parikh, Joseph Park, Ivana Nikolic, Richard Channick, Paul B. Yu, Teresa De Marco, Priscilla Hsue, STEPHEN Y. CHAN. Coordinated modulation of circulating miR-21 in HIV, HIV-associated pulmonary arterial hypertension, and HIV/HCV co-infection. Journal of Acquired Immune Deficiency Syndromes. 70(3):236-41 (2015).

11. Bertero T, Cottrill KA, Lu Y, Haeger CM, Dieffenbach P, Annis S, Hale A, Bhat B, Kaimal V, Zhang YY, Graham BB, Kumar R, Saggar R, Saggar R, Wallace WD, Ross DJ, Black SM, Fratz S, Fineman JR, Vargas SO, Haley KJ, Waxman AB, Chau BN, Fredenburgh LE, STEPHEN Y. CHAN. Matrix remodeling promotes pulmonary hypertension through feedback mechanoactivation of the YAP/TAZ-miR-130/301 circuit. Cell Reports 13(5):1016-1032 (2015).

12.  Thomas Bertero, William M. Oldham, Katherine A. Cottrill, Sabrina Pisano, Rebecca R. Vanderpool, Qiujun Yu, Jingsi Zhao, Yiyin Tai, Ying Tang, Ying-Yi Zhang, Sofiya Rehman, Masataka Sugahara, Zhi Qi, John Gorcsan III, Sara O. Vargas, Rajan Saggar, Rajeev Saggar, W. Dean Wallace, David J. Ross, Kathleen J. Haley, Aaron B. Waxman, Victoria N. Parikh, Teresa De Marco, Priscilla Y. Hsue, Alison Morris, Marc A. Simon, Karen A. Norris, Cedric Gaggioli, Joseph Loscalzo, Joshua Fessel, STEPHEN Y. CHAN. Vascular stiffness drives metabolic alterations in pulmonary hypertension.  The Journal of Clinical Investigation.  126(9):3313-35 (2016).

In studying emerging mechanisms by which the biophysical properties of extracellular matrix (ECM) control pulmonary vascular metabolic processes, we have found that vascular ECM remodeling and stiffening are early and pervasive processes that promote PH.  Moreover, we found that mechanoactivation of YAP/TAZ in stiff ECM modulated metabolic enzymes including lactate dehydrogenase A (LDHA), pyruvate carboxylase (PC), and glutaminase (GLS1), thus inducing glutaminolysis, and anaplerosis and sustaining proliferation and migration with increased glycolysis.  Our findings define the activation of glutaminolysis and anaplerosis as a paradigm by which vessel stiffness can stimulate proliferation in PH.

13.  Yu Q, Tai YY, Tang Y, Zhao J, Negi V, Culley MK, Pilli J, Sun W, Brugger K, Mayr J, Saggar R, Saggar R, Wallace WD, Ross DJ, Waxman AB, Wendell SG, Mullett SJ, Sembrat J, Rojas M, Khan OF, Dahlman JE, Sugahara M, Kagiyama N, Satoh T, Zhang M, Feng N, Gorcsan Iii J, Vargas SO, Haley KJ, Kumar R, Graham BB, Langer R, Anderson DG, Wang B, Shiva S, Bertero T, Chan SY.  Circulation. 2019 Feb 14. doi: 10.1161/CIRCULATIONAHA.118.035889. [Epub ahead of print].   PMID: 30759996

In this study, we demonstrate that epigenetic and hypoxic repression of the iron-sulfur biogenesis protein BOLA3 promotes pulmonary artery endothelial metabolic re-programming and dysfunction. To do so, BOLA3 deficiency induces alterations of mitochondrial electron transport, glycolysis, and fatty acid oxidation. BOLA3 deficiency also represses lipoate biosynthesis, thus inhibiting the glycine cleavage system, increasing glycine accumulation, and promoting endothelial proliferation. In vivo, we find that BOLA3 deficiency is both necessary and sufficient to regulate endothelial glycine metabolism and to promote hemodynamic and histologic manifestations of pulmonary hypertension. These findings define BOLA3 as a crucial lynchpin connecting oxidative metabolism and glycine homeostasis with endothelial dysfunction in pulmonary hypertension. These results provide a molecular explanation for the enigmatic clinical associations linking pulmonary hypertension with hyperglycinemic syndromes and mitochondrial disorders, such as those driven by endogenous BOLA3 mutations. These findings also identify novel metabolic targets, including those involved in epigenetics, iron-sulfur biogenesis, and glycine homeostasis, for diagnostic and therapeutic development in this devastating disease.