Polyamine regulatory pathways as pharmacologic targets in pulmonary arterial hypertension.
Decades of studies in animal models and in humans with pulmonary artery hypertension have left little doubt that the processes culminating in hyper-tensive pulmonary vascular remodeling and sustained increases in pulmonary vascular resistance are complex. Modulations in phenotype, proliferative state, and survival of multiple lung vascular cell populations, changes in the local milieu of growth and differentiation factors, and alterations in the extracellular connective tissue environment all seem to contribute to the pathogenesis of the disorder. From a pharmacologic vantage point, identifying which of these is the most suitable target is challenging. Our studies are predicated on the concept that pathways "distal" in the signaling cascades - upon which multiple stimuli dictating vascular cell structure and function converge - might be effective drug targets in PAH. In this regard, we found that the polyamines, putrescine, spermidine, and spermine, a family of low molecular weight organic cations required for cell growth and differentiation, along with their biosynthetic pathways and transmembrane transporters, are altered in rational animal models of pulmonary arterial hypertension. In this article, we summarize these data incriminating polyamines and their regulatory pathways in hypertensive pulmonary vascular disease and advance the contention that polyamine synthesis inhibitors and transport blockers should indeed be considered for clinical trials in human pulmonary arterial hypertension.
Gillespie
Mark N
MN
Department of Pharmacology and Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL, 36688, USA. mgillesp@jaguar1.usouthal.edu
Olson
Jack W
JW
D000818:Animals; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000860:Hypoxia / Q000503:physiopathology; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016686:Monocrotaline / Q000494:pharmacology; D011073:Polyamines / Q000378:metabolism / Q000627:therapeutic use
D011073:Polyamines; D016686:Monocrotaline