Dr. Dai's article: Therapeutic Targeting of Vascular Remodeling and Right Heart Failure in Pulmonary Arterial Hypertension with a HIF-2α Inhibitor., American Journal of Respiratory and Critical Care Medicine, 2018 (DOI: 10.3410/f.733483017.793554432), has been recommended in F1000Prime as being of special significance in its field by F1000 Faculty Member Larissa Shimoda.
Full recommendation and comments were showed below (https://f1000.com/prime/733483017). Shimoda L: F1000Prime Recommendation of [Dai Z et al., Am J Respir Crit Care Med 2018 198(11):1423-1434]. In F1000Prime, 21 Dec 2018; 10.3410/f.733483017.793554432
Despite years of research, pulmonary hypertension remains a condition with limited treatment options and significant morbidity and mortality. One reason for the lack of new therapies is an incomplete understanding of the cellular mechanisms involved in the pathogenesis of disease. Over the years, substantial data have accumulated pointing to a role for the transcription factors, hypoxia-inducible factors (HIFs), in the development of pulmonary hypertension, although which HIF (HIF-1 or HIF-2) in which cell type (smooth muscle, endothelial cells, fibroblasts, immune cells) and at which time point (early or late disease) is important remains unclear.
Thus, the objective of this manuscript was to identify whether HIF-1 and/or HIF-2 were upregulated in samples from patients and experimental animals with pulmonary hypertension and to evaluate the effects of a small molecule inhibitor of HIF-2 on pulmonary hypertension in pre-clinical models. The study used protocols to evaluate both prevention (beginning treatment at the time of insult) and reversal (beginning treatment after pulmonary hypertension was established) in multiple rodent model, assessing survival, remodeling of the pulmonary vasculature (a hallmark of disease) and cardiac remodeling and contractility. The drug had an impressive effect on mortality, and was successful in both preventing and slowing progression of increased pressures, remodeling and right heart hypertrophy. Given the predominance of HIF-2 expression in the endothelium, the authors conclude that targeting overexpression of HIF-2 in the endothelial cells could be effective for treatment of pulmonary hypertension.
This comprehensive set of studies adds to our knowledge regarding a role for HIFs in pulmonary hypertension. While it is clear that pre-clinical data are just a first step and longer term evaluation of the safety and efficacy of inhibiting this pathway is needed, the results are intriguing and provide proof-of-concept that HIF-2 could be a potentially targetable pathway for intervention.
