Dissertation Defense: From Measurement to Policy: Impact of Sleep and Circadian Rhythm Disruption on Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Implications
Dissertation Defense: Impact of Sleep and Circadian Rhythm Disruption on Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Implications
Seun Imani
Graduate Student, Translational Biology, Medicine, and Health
Graduate Research Assistant, Sassi Lab, Fralin Biomedical Research Institute at VTC
April 29, 2026, at 1 p.m.
Room 1101, 4 Riverside Circle
About this Dissertation
Background and Aim: Pulmonary arterial hypertension (PAH) is a progressive and deadly cardiopulmonary disease characterized by remodeling of pulmonary vessels and right ventricular dysfunction. Despite available treatments, the death rate remains high among patients. Emerging clinical data show a high prevalence of poor sleep quality in patients with PAH. However, it is still unclear whether or how sleep disruption contributes to PAH progression. Additionally, the role of the molecular clock in various diseases is well documented; however, how this clock affects pulmonary artery smooth muscle cell (PASMC) function and PAH remains largely underexplored.
Methods: Imani, mentored by Yassine Sassi, used two models of sleep disruption (sleep fragmentation and chronic jet lag), four mouse models of PAH, and conducted hemodynamic and histomorphometric analyses to determine the effect of sleep disturbance on PAH. Bulk RNA sequencing, immunostaining, and immunoblotting assays were employed to investigate signaling mechanisms. Electroencephalography and electromyography (EEG/EMG) telemetry were used to assess sleep architecture in PAH mouse models. Imani then used melatonin and clodronate interventions to examine the roles of sleep modulation and inflammation reduction in PAH. The clock genes BMAL1 and CLOCK (key drivers of the molecular clock) in PASMCs were defined by synchronizing cells from healthy donors and PAH patients, followed by time-point qPCR. Finally, Imani explored the role of the clock gene in PAH using smooth muscle cell (SMC)-specific Bmal1 knockout mice.
Results: Imani's data showed that sleep disruption significantly aggravated PAH, characterized by increased right ventricular systolic pressure (RVSP), enhanced RV hypertrophy, and greater pulmonary vascular remodeling. RNA-seq and immunostaining analyses of lung tissues revealed that sleep disruption caused substantial enrichment of inflammatory pathways, macrophage accumulation, and elevated levels of inflammatory cytokines. Further in vitro studies indicated that inflammatory cytokines markedly activated the IL6/STAT3/TGF-β/SMAD2/3 pathway in PASMCs, a finding also observed in vivo. EEG/EMG measurements demonstrated that PAH leads to considerable sleep disruption in PAH mice. The combination of melatonin and clodronate significantly reduced PAH. PASMCs from PAH patients exhibited disrupted oscillations of BMAL1 and CLOCK, and SMC-specific deletion of Bmal1 protected mice from PAH symptoms.
Conclusion: This dissertation shows that PAH and sleep disruption form a self-reinforcing pathological cycle, where PAH causes sleep disruption, and disturbed sleep further worsens PAH phenotypes and amplifies disease progression. Combining sleep-promoting and anti-inflammatory strategies attenuates PAH in preclinical models. Concurrently, the circadian molecular clock component BMAL1 is dysregulated in PASMCs, leading to PASMC hyperproliferation through the cell cycle checkpoint, and SMC-specific inhibition of Bmal1 offers a promising therapy for PAH.
More About the Candidate and Project
Education
Virginia Tech, Translational Biology, Medicine, and Health, Ph.D. Candidate
Ahmadu Bello University, B.Sc, Human Anatomy
Training
Graduate Research Assistant, Sassi Lab, Fralin Biomedical Research Institute at VTC
Mentor
Yassine Sassi, Ph.D., Assistant Professor, Fralin Biomedical Research Institute at VTC
Committee Members
- Clement Vinauger, Ph.D., Associate Professor, Department of Biochemistry, College of Agriculture and Life Sciences
- Sameh Aziz, M.D., Professor, Internal Medicine, Virginia Tech Carilion School of Medicine; Pulmonary and Critical Care Medicine, Carilion Clinic
- Alexandra DiFeliceantonio, Ph.D., Assistant Professor and Interim Co-director, Center for Health Behaviors Research, Fralin Biomedical Research Institute at VTC
- Scott Johnstone, Ph.D., Assistant Professor, Fralin Biomedical Research Institute at VTC
Publications
Aborode, A. T., Onigbinde, S. B., Sanusi, K. O., Alaba, N., Rasaq-Lawal, A. H., Obadawo, B.S., Olatoyosi, A., Adeniran-Obey, S. O., Onwukwe, V., Asogwa, U., Arinola, R. I., Imani, S. I., Fasawe, A. S., Sodiya, I., Adeyemi, S. B., & Batiha, G. E. Understanding the role of genetic susceptibility (ACE2 and TMPRSS2) in COVID-19. Egyptian Journal of Basic and Applied Sciences, 9(1), 43–50.
Imani, S., Wallace, R., Sassi, Y. In Vitro Experimental Approach for Studying Human Pulmonary Artery Smooth Muscle Cells and Endothelial Cells Proliferation and Migration. Methods Mol Biol. 2024;2803:49-58. doi: 10.1007/978-1-0716-3846-0_4. PMID: 38676884.
Cacheux M, Strauss B, Parajuli S, Halouani A, Katz MG, Imani S, Antar S, Bedoya N, Hadri L, Akar FG, Sassi Y. Extracellular-cAMP suppresses pulmonary arterial hypertension-induced ventricular arrhythmias. J Mol Cell Cardiol. 2026 Feb;211:109-118. doi: 10.1016/j.yjmcc.2025.12.004. Epub 2025 Dec 8. PMID: 41371472.
Seun Imani, Aymen Halouani, Neil J. Kelly, Jacob Dahlka, Nathan Burgess, Samar A Antar, You-Yang Zhao, James D West, Matthew Weston, Stephen Y. Chan, and Yassine Sassi. A vicious cycle of sleep disruption and pulmonary arterial hypertension mediated by inflammation and vascular remodeling. Manuscript In review
Nestor Bedoya and Seun Imani, Spencer R. Marsh, Emerson Obus, Jacob Dahlka, Eric Mensah, Claire Beard, Golnar Eftekhari, Emma E. Hendrix, Sabrina La Salvia, Susmita Sahoo, Stefano Toldo, Robert G. Gourdie, and Yassine Sassi. Myocardial Bioavailability of Bovine Milk Extracellular Vesicles-Derived MicroRNAs. Manuscript In Review
Samar A Antar, Eric Mensah, Jacob Dahlka, Michael Aziz, Aymen Halouani, Seun Imani, Aanandi Parashar, Ahmed A Raslan, Robert Benezra, Diego Fraidenraich, Giovanni Ligresti, Yassine Sassi. A Simultaneous Inhibition of ID1 and ID3 Protects Against Pulmonary Fibrosis. Manuscript In Review
Aymen Halouani, Eric Mensah, Mariem Ben Rhouma, Zaujia Athumani, Michael G. Katz, Seun Imani, Samar A Antar, Katherine Jankowski, Maryam Mansoori, Vicki Rosen, Kiyotake Ishikawa, Lahouaria Hadri, and Yassine Sassi. Paracrine Action of Bone Morphogenetic Protein 3 in Pulmonary Arterial Hypertension. In Review
Seun Imani, Aymen Halouani, and Yassine Sassi. Therapeutic Potential of Circadian Clock Component BMAL1 in Pulmonary Arterial Hypertension. Manuscript In Preparation
Oral Presentations
Imani, S. et al. (2023). Impact of Sleep Disturbance on Cardiopulmonary Diseases. Research in Progress, Fralin Biomedical Research Institute, Virginia Tech.
Imani, S. et al. (2024). Impact of Sleep Disturbance on Pulmonary Arterial Hypertension. Research in Progress, Fralin Biomedical Research Institute, Virginia Tech.
Imani, S. et al. (2025). A vicious cycle of sleep disruption and pulmonary arterial hypertension mediated by inflammation and vascular remodeling. Research in Progress, Fralin Biomedical Research Institute, Virginia Tech.
Conference - Poster
Imani, S. et al. (2024). Extracellular-cAMP Suppresses Pulmonary Arterial Hypertension-induced Ventricular Arrhythmias. American Thoracic Society International Conference, San Diego, CA.
Imani, S. et al. (2026). Bidirectional Crosstalk Between Sleep and Pulmonary Arterial Hypertension. Poster accepted for presentation at the American Thoracic Society International Conference, Orlando, FL. May 2026
- Shark Tank Commercialization Pitch Competition, 1st Place, Illuminostics (2021)
- Biotech Scholar, Scholar Mentoring and Development Program (2024)
- Virginia Tech Graduate and Professional Student Senate Travel Award (2024)
- American Thoracic Society Student Scholar Award (2024)
- American Thoracic Society Underrepresented Trainee Development Scholarship (2024)
- American Heart Association Predoctoral Fellowship (2025)
- National Research Service Award, NIH F31 Fellowship (2025)
- TBMH Student of the Year, Science Pillar (2025)
- Virginia Tech Graduate and Professional Student Senate Travel Award (2026)
- Volunteer, Rescue Mission Thanksgiving Feast, 2024
- Volunteer Judge, FBRI Summer Research Programs Symposium, 2024
- Volunteer, Flip the Fair 2023
- Volunteer, 2nd Annual Biomedical Professional. Development Symposium, 2023