Arnab Ghosh Laboratory

Research

Our overall research interest is to investigate how maturation of specific hemeproteins maybe adversely affected in cardiopulomonary diseases and inflammatory myopathies. Studying the disease pathogenesis would then enable us to design strategies for therapeutic intervention. We are focusing on a vasodilatory hemeprotein,.soluble guanylate cyclase (sGC) and investigating how this heme maturation maybe affected in cardiopulmonary diseases such as pulmonary arterial hypertension (PAH) and asthma. From our basic research in hemeprotein maturation, we found thathsp90 interacted almost exclusively with heme-free apo-inducible nitric oxide synthase (apo-iNOS)/apo-sGCβ1 in cells and then drove heme-insertion into these proteins by a ATP dependent process. For hemeprotein sGC we established that sGCβ1-hsp90 interactions in cells is mutually exclusive or holds a reciprocal relationship with respect to sGC-α1β1 heterodimerization and this can be a marker of sGC activity. A strong sGC heterodimer maybe indicative of healthy sGC and a weak heterodimer with strong sGCβ1-hsp90 interaction would mimic a diseased state where sGC is heme-free and is immune to activation by its natural activator nitric oxide (NO). In our findings published few years back, we find that due to high levels of NO, lung sGC is dysfunctional in asthma and impedes bronchodilation. Interestingly we also established that low nitric oxide (NO) levels can drive heme-insertion into sGC-β1 and cause an elevated sGCα1β1 heterodimer, implying that NO levels are critical to sGC function, in healthy and diseased states. In this study the hallmarks of sGC dysfunction in asthma were similar to what we previously found, a weak sGC-α1β1 heterodimer and a strong sGCβ1-hsp90 interaction. We can now imprint this sGC dysfunction as a disease indicator in asthma.

More recently we found that hsp90 can also promote hemoglobin (Hb) and myoglobin (Mb) heme- maturation following a similar mechanism further reinforcing the concept of hsp90-client protein maturation. We can now investigate the implications of these hsp90 promoted globin heme-maturation events in diseased conditions where these globins are dysfunctional or dysregulated, in order to enable development of novel strategies for therapeutic intervention.

Grant News:
The proposal entitled “Nitric oxide induced soluble guanylate cyclase dysfunction or activation: Implications as disease indicators or in therapy”, was awarded NIH grants in form of a one year R56 and a succeeding RO1 (over 2 million dollars) from National heart lung blood institute to study the effects of variable nitric oxide levels on soluble guanylate cyclase function in the lungs. The above funded proposal builds on our findings (Ref. 6, under selected publications) that describe a new way of treating asthma by triggering bronchodilation by an alternative pathway in the airway (the NO-sGC-cGMP pathway), using soluble guanylate cyclase (sGC) activators that can directly activate the sGC enzyme. We propose several translational approaches to decipher molecular mechanisms which make lung sGC dysfunctional under high NO. Based on our previous studies on hemeprotein maturation (Ref. 7) we find that low levels of NO can trigger a rapid buildup of sGC-α1β1 heterodimer by inserting heme into the β1 subunit. We further propose to exploit this beneficial effect of low NO to better stabilize the human lung sGC heterodimer formation, decipher molecular mechanisms causing heme-free sGC accumulation and will explore pathways to restore sGC dysfunction in airway smooth muscle cells (ASMCs) from asthma.

Selected Publications

Mamta P. Sumi, Blair Tupta, Kevin Song, Lori Mavrakis, Suzy Comhair, Serpil C. Erzurum, Xuefeng Liu, Dennis J Stuehr and Arnab Ghosh. Expression of soluble guanylate cyclase (sGC) and its ability to form a functional heterodimer are crucial for reviving the NO-sGC signaling in PAH.Free Radic Biol Med. 2024 Nov 6;225:846-855. doi:10.1016/j.freeradbiomed.2024.11.009. Online ahead of print. PMID: 39515593

Mamta P Sumi, Rosemary Westcott, Eric Stuehr, Chaitali Ghosh, Dennis J Stuehr, Arnab Ghosh. Regional variations in allergen-induced airway inflammation correspond to changes in soluble guanylyl cyclase heme and expression of heme oxygenase-1. FASEB J.  2024 Mar 31;38(6):e23572.  doi: 10.1096/fj.202301626RRR. Affiliations expand. PMID: 38512139. PMCID: PMC10977653 (available on 2025-03-31) DOI: 10.1096/fj.202301626RRR. 

Sumi MP, Tupta B, Roychowdhury S, Comhair S, Asosingh K, Stuehr DJ, Erzurum SC and Ghosh A*. Hemoglobin resident in the lung epithelium is protective for smooth muscle soluble guanylate cyclase function. Redox Biol. 2023 Jul:63:102717.  doi: 10.1016/j.redox.2023.102717. Epub 2023 Apr 25.  PMID: 37120930. PMCID: PMC10172757:  DOI: 10.1016/j.redox.2023.102717. 

Sumi, MP, Tupta B and Ghosh A*. Nitric Oxide Trickle Drives Heme into Hemoglobin and Muscle Myoglobin. Cells 2022 11:2838. doi: 10.3390/cells11182838. PMID: 36139413. 

Stuehr DJ, Dai Y, Biswas P, Sweeny EA, Ghosh A. New roles for GAPDH, Hsp90, and NO in regulating heme allocation and hemeprotein function in mammals. Biol Chem. 2022 Nov 25;403(11-12):1005-1015. doi: 10.1515/hsz-2022-0197. Print 2022 Nov 25. Review. PubMed PMID: 36152339.

Ghosh A, Sumi MP, Tupta B, Okamoto T, Aulak K, Tsutsui M, Shimokawa H, Erzurum SC, Stuehr DJ. Low levels of nitric oxide promotes heme maturation into several hemeproteins and is also therapeutic. Redox Biol. 2022 Oct;56:102478. doi: 10.1016/j.redox.2022.102478. Epub 2022 Sep 13. PubMed PMID: 36116161; PubMed Central PMCID: PMC9486108. -Sumi MP, Tupta B, Ghosh A. Nitric Oxide Trickle Drives Heme into Hemoglobin and Muscle Myoglobin. Cells. 2022 Sep 12;11(18). doi: 10.3390/cells11182838. PubMed PMID: 36139413; PubMed Central PMCID: PMC9496899.

Sumi MP, Ghosh A. Hsp90 in Human Diseases: Molecular Mechanisms to Therapeutic Approaches. Cells. 2022 Mar 12;11(6). doi: 10.3390/cells11060976. Review. PubMed PMID: 35326427; PubMed Central PMCID: PMC8946885.

Tupta B, Stuehr E, Sumi MP, Sweeny EA, Smith B, Stuehr DJ, Ghosh A. GAPDH is involved in the heme-maturation of myoglobin and hemoglobin. FASEB J. 2022 Feb;36(2):e22099. doi: 10.1096/fj.202101237RR. PubMed PMID: 34972240; PubMed Central PMCID: PMC9239731.

Ghosh A, Koziol-White CJ, Jester WF Jr, Erzurum SC, Asosingh K, Panettieri RA Jr, Stuehr DJ. An inherent dysfunction in soluble guanylyl cyclase is present in the airway of severe asthmatics and is associated with aberrant redox enzyme expression and compromised NO-cGMP signaling. Redox Biol. 2021 Feb;39:101832. doi: 10.1016/j.redox.2020.101832. Epub 2020 Dec 13. PubMed PMID: 33360351; PubMed Central PMCID: PMC7772568. 

C. J. Koziol-White*, A. Ghosh, S. C. Erzurum, P. Sandner, D. J. Stuehr, and R. A. Panettieri, Jr. Soluble guanylate cyclase agonists induce bronchodilation in human small airways. Am J Respir Cell Mol Biol. 62 (2020) 43-48. PMID: 31340135

A. Ghosh* and D. J. Stuehr. Hsp90 and Its Role in Heme-Maturation of Client Proteins: Implications for Human Diseases. Chapter 12 (Book: Heat Shock Proteins, Vol 19, 2019, Heat Shock Protein 90 in Human Diseases and Disorders, Springer Nature Publications).

A. Ghosh*, Y. Dai, P. Biswas and D. J. Stuehr*. Myoglobin maturation is driven by the hsp90 chaperone machinery and by soluble guanylyl cyclase. FASEB J 33 (2019), 9885-9896. PMID: 31170354 

A. Ghosh*, G. Garee, E. A. Sweeny, Y. Nakamura and D. J. Stuehr.* Hsp90 chaperones hemoglobin maturation in erythroid and non-erythroid cells. Proc Natl Acad Sci U S A. 115 (2018) E1117-E1126. PMID: 29358373. Read Story (LRI News)

A. Ghosh and D. J. Stuehr. Regulation of sGC via hsp90, cellular heme, sGC agonists, and NO: New pathways and clinical perspectives. Antioxid Redox Signal. 26 (2017),182-190. PMID:26983679. Article featured in the cover of the Feb 2017 issue of the journal.

A. Ghosh,C. J. Koziol-White, A. Kewal, G. Cheng, L. Ruple, D. Groneberg, A. Friebe, S. Comhair, J. P. Stasch, R. A. Panettieri, M. A. Aronica, S. C. Erzurum and D. J. Stuehr.Soluble guanylate cyclase as an alternative target for bronchodilator therapy in asthma. Proc Natl Acad Sci U S A. 113 (2016), E2355-E2362. PMID: 27071111. Read Story (Cleveland Clinic Newsroom)

A. Ghosh, J.P. Stasch, A. Papapetropoulos and D. J. Stuehr. Nitric Oxide and Heat Shock Protein 90 Activate Soluble Guanylate Cyclase by Driving Rapid Change in Its Subunit Interactions and Heme Content. J Biol Chem. 289 (2014), 15259-15271. PMID: 24733395