SELECTED PUBLICATIONS

1. CHAN SY, Zhang YY, Hemann C, Mahoney CE, Zweier JL, Loscalzo J. MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metab. 2009 Oct;10(4):273-84. PMID: 19808020; PMCID: PMC2759401.

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. Baggish AL, Hale A, Weiner RB, Lewis GD, Systrom D, Wang F, Wang TJ, CHAN SY. Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training. J Physiol. 2011 Aug 15;589(Pt 16):3983-94. PMID: 21690193; PMCID: PMC3179997.

3. Parikh VN, Jin RC, Rabello S, Gulbahce N, White K, Hale A, Cottrill KA, Shaik RS, Waxman AB, Zhang YY, Maron BA, Hartner JC, Fujiwara Y, Orkin SH, Haley KJ, Barabási AL, Loscalzo J, CHAN SY. MicroRNA-21 integrates pathogenic signaling to control pulmonary hypertension: results of a network bioinformatics approach. Circulation. 2012 Mar 27;125(12):1520-32. PMID: 22371328; PMCID: PMC3353408.

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. Snow JW, Hale AE, Isaacs SK, Baggish AL, CHAN SY. Ineffective delivery of diet-derived microRNAs to recipient animal organisms. RNA Biol. 2013 Jul;10(7):1107-16. PMID: 23669076; PMCID: PMC3849158.

5. Baggish AL, Park J, Min PK, Isaacs S, Parker BA, Thompson PD, Troyanos C, D’Hemecourt P, Dyer S, Thiel M, Hale A, CHAN SY. Rapid upregulation and clearance of distinct circulating microRNAs after prolonged aerobic exercise. J Appl Physiol (1985). 2014 Mar 1;116(5):522-31. PMID: 24436293; PMCID: PMC3949215.

6. 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. J Clin Invest. 2014 Aug;124(8):3514-28.  Erratum in: J Clin Invest. 2022 May 16;132(10): PMID: 24960162; PMCID: PMC4109523.

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. Hale A, Lee C, Annis S, Min PK, Pande R, Creager MA, Julian CG, Moore LG, Mitsialis SA, Hwang SJ, Kourembanas S, CHAN SY. An Argonaute 2 switch regulates circulating miR-210 to coordinate hypoxic adaptation across cells. Biochim Biophys Acta. 2014 Nov;1843(11):2528-42. PMID: 24983771; PMCID: PMC4158026.

8. Bertero T, Cottrill K, Krauszman A, Lu Y, Annis S, Hale A, Bhat B, Waxman AB, Chau BN, Kuebler WM, CHAN SY. The microRNA-130/301 family controls vasoconstriction in pulmonary hypertension. J Biol Chem. 2015 Jan 23;290(4):2069-85. PMID: 25505270; PMCID: PMC4303661.

9. White K, Lu Y, Annis S, Hale AE, Chau BN, Dahlman JE, Hemann C, Opotowsky AR, Vargas SO, Rosas I, Perrella MA, Osorio JC, Haley KJ, Graham BB, Kumar R, Saggar R, Saggar R, Wallace WD, Ross DJ, Khan OF, Bader A, Gochuico BR, Matar M, Polach K, Johannessen NM, Prosser HM, Anderson DG, Langer R, Zweier JL, Bindoff LA, Systrom D, Waxman AB, Jin RC, CHAN SY. Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension. EMBO Mol Med. 2015 Jun;7(6):695-713. PMID: 25825391; PMCID: PMC4459813.

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. Parikh VN, Park J, Nikolic I, Channick R, Yu PB, De Marco T, Hsue PY, CHAN SY. Brief Report: Coordinated Modulation of Circulating miR-21 in HIV, HIV-Associated Pulmonary Arterial Hypertension, and HIV/Hepatitis C Virus Coinfection. J Acquir Immune Defic Syndr. 2015 Nov 1;70(3):236-41. PMID: 26473639; PMCID: PMC4610144.

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, CHAN SY. Matrix Remodeling Promotes Pulmonary Hypertension through Feedback Mechanoactivation of the YAP/TAZ-miR-130/301 Circuit. Cell Rep. 2015 Nov 3;13(5):1016-32.  PMID: 26565914; PMCID: PMC4644508.

12. Bertero T, Oldham WM, Cottrill KA, Pisano S, Vanderpool RR, Yu Q, Zhao J, Tai Y, Tang Y, Zhang YY, Rehman S, Sugahara M, Qi Z, Gorcsan J 3rd, Vargas SO, Saggar R, Saggar R, Wallace WD, Ross DJ, Haley KJ, Waxman AB, Parikh VN, De Marco T, Hsue PY, Morris A, Simon MA, Norris KA, Gaggioli C, Loscalzo J, Fessel J, CHAN SY. Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension. J Clin Invest. 2016 Sep 1;126(9):3313-35. PMID: 27548520; PMCID: PMC5004943.

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 J 3rd, Vargas SO, Haley KJ, Kumar R, Graham BB, Langer R, Anderson DG, Wang B, Shiva S, Bertero T, CHAN SY. BOLA (BolA Family Member 3) Deficiency Controls Endothelial Metabolism and Glycine Homeostasis in Pulmonary Hypertension. Circulation. 2019 May 7;139(19):2238-2255. PMID: 30759996; PMCID: PMC6519484.

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.

14.  Pi H, Kosanovich CM, Handen A, Tao M, Visina J, Vanspeybroeck G, Simon MA, Risbano MG, Desai A, Mathier MA, Rivera-Lebron BN, Nguyen Q, Kliner J, Nouraie M, CHAN SY (Senior Author). Outcomes of Pulmonary Arterial Hypertension are Improved in a Specialty Care Center. Chest. 2020; 158(1):330-340. Pubmed PMID: 32109446; PMCID: PMC7339236.

Editorial: Chakinala MM and Farber HW. Pulmonary Arterial Hypertension and Specialty Care Centers: We Had a Feeling; Now We Have Data. Chest. 2020; 158(1):28-30. Pubmed PMID: 32654707.

15.  Zhao J, Florentin J, Tai YY, Torrino, S, Ohayon L, Brzoska T, Tang Y, Yang J, Negi V, Woodcock CC, Risbano MG, Nouraie SM, Sundd P, Bertero T, Dutta P, CHAN SY (Senior Author). Long range endocrine delivery of circulating miR-210 to endothelium promotes pulmonary hypertension. Circulation Research. 2020; 127(5):677-692. Pubmed PMID: 32493166; PMCID: PMC7429300.

Editorial: Leopold JA. Endocrine Delivery of MicroRNA-210: A Trusted Traveler that Mediates Pulmonary Hypertension. Circulation Research. 2020; 127(5):693-695. Pubmed PMID: 32790524; PMCID: PMC7880541.

16.  Sun W, Tang Y, Tai YY, Handen A, Zhao J, Speyer G, Al Aaraj Y, Watson A, Romanelli ME, Sembrat J, Rojas M, Simon MA, Zhang Y, Lee J, Xiong Z, Dutta P, Vasamsetti SB, McNamara D, McVerry B, McTiernan CF, Sciurba FC, Kim S, Smith KA, Mazurek JA, Han Y, Vaidya A, Nouraie SM, Kelly NJ, CHAN SY (Senior Author). SCUBE1 Controls BMPR2-Relevant Pulmonary Endothelial Function: Implications for Diagnostic Marker Development in Pulmonary Arterial Hypertension. JACC Basic to Translational Science. 2020; 5(11):1073-109. Pubmed PMID: 33294740; PMCID: PMC7691287.

*Winner of 2020 Young Author Achievement Award, JACC: Basic to Translational Science

Editorial: Gomez-Arroyo J, Voelkel NF, Abbate A. SCUBE Diving: Biomarker Discovery for Pulmonary Hypertension from Bench to Bedside. JACC Basic to Translational Science. 2020; 5(11):1093-1094. Pubmed PMID: 33296445; PMCID: PMC7691277.

17.  Culley MK, Zhao J, Tai YY, Tang Y, Perk D, Negi V, Yu Q, Woodcock C-SC, Handen A, Speyer G, Kim S, Lai Y-C, Satoh T, Watson A, Al Aaraj Y, Sembrat J, Rojas M, Goncharov D, Goncharova EA, Khan OF, Anderson DG, Dahlman JE, Gurkar A, Lafyatis R, Fayyaz AU, Redfield MM, Gladwin MT, Rabinovitch M, Gu M, Bertero T, CHAN SY (Senior Author). Frataxin deficiency promotes endothelial senescence in pulmonary hypertension. Journal of Clinical Investigation. 2021; 131(11):e136459. Pubmed PMID: 33905372; PMCID: PMC8159699.

Editorial: Lawrie A and Francis SE. Frataxin and endothelial cell senescence in pulmonary hypertension. Journal of Clinical Investigation. 2021; 131(11):e149721. Pubmed PMID: 34060487; PMCID: PMC8159686.

18.  Negi V, Yang J, Speyer G, Pulgarin A, Handen A, Zhao J, Tai YY, Tang Y, Culley MK, Yu Q, Forsythe P, Gorelova A, Watson AM, Al Aaraj Y, Satoh T, Sharifi-Sanjani M, Rajaratnam A, Sembrat J, Provencher S, Yin X, Vargas SO, Rojas M, Bonnet S, Torrino S, Wagner BK, Schreiber SL, Dai M, Bertero T, Al Ghouleh I*, Kim S*, CHAN SY (*Co-Senior Authors). Computational repurposing of therapeutic small molecules from cancer to pulmonary hypertension. Science Advances. 2021; 7:eabh3794. Pubmed PMID: 34669463; PMCID: PMC8528428.

19.  Alotaibi M, Shao J, Pauciulo MW, Nichols WC, Hemnes AR, Malhotra A, Kim NH, Yuan JX-J, Fernandes T, Kerr KM, Alshawabkeh L, Desai AA, Bujor AM, Lafyatis R, Watrous JD, Long T, Cheng S, CHAN SY*, Jain M* (*Co-Senior Authors). Metabolomic Profiles Differentiate Scleroderma-PAH from Idiopathic PAH and Correspond with Worsened Functional Capacity. Chest. 2022; S0012-3692(22)03706-0. Pubmed PMID: 36087794; PMC Journal – In Process.

20.  Hafeez N, Kirillova A, Yue Y, Rao RJ, Kelly NJ, El Khoury W, Al Aaraj Y, Tai YY, Handen A, Tang Y, Jiang D, Wu T, Zhang Y, McNamara D, Kudryashova TV, Goncharova EA, Goncharov D, Bertero T, Nouraie M, Li G, Sun W*, CHAN SY* (*Co-Senior Authors). Single Nucleotide Polymorphism rs9277336 Controls the Nuclear Alpha Actinin 4-Human Leukocyte Antigen-DPA1 Axis and Pulmonary Endothelial Pathophenotypes in Pulmonary Arterial Hypertension. J Am Heart Assoc. 2023 Apr 4;12(7):e027894. doi: 10.1161/JAHA.122.027894. Epub 2023 Mar 28. PMID: 36974749; PMCID: PMC10122886.