TY - JOUR
T1 - Activation of the metabolic master regulator PPARg
T2 - A potential pioneering therapy for pulmonary arterial hypertension
AU - Hansmann, Georg
AU - Calvier, Laurent
AU - Risbano, Michael G.
AU - Chan, Stephen Y.
N1 - Funding Information:
Supported by the German Research Foundation (DFG; HA4348/2-2 and HA4348/6 KFO311), Kinderherzen (W-H-001-2014), and the European Pediatric Pulmonary Vascular Disease Network (www.pvdnetwork.org) (G.H.). L.C. is the recipient of a DFG Postdoctoral Fellowship (CA 1303/1-1). S.Y.C. was supported by National Institutes of Health grants R01 HL124021, HL 122596, HL 138437, and UH2 TR002073 as well as the American Heart Association Established Investigator Award (18EIA33900027).
Publisher Copyright:
Copyright © 2020 by the American Thoracic Society
PY - 2020
Y1 - 2020
N2 - Translational research is essential to the development of reverse-remodeling strategies for the treatment of pulmonary vascular disease, pulmonary hypertension, and heart failure via mechanistic in vivo studies using animal models resembling human pulmonary arterial hypertension (PAH), cardiovascular remodeling, and progressive right heart failure. Since 2007, peroxisome proliferator–activated receptor g (PPARg) agonists have emerged as promising novel, antiproliferative, antiinflammatory, insulin-sensitizing, efficient medications for the treatment of PAH. However, early diabetes study results, their subsequent misinterpretations, errors in published review articles, and rumors regarding potential adverse effects in the literature have dampened enthusiasm for considering pharmacological PPARg activation for the treatment of cardiovascular diseases, including PAH. Most recently, the thiazolidinedione class PPARg agonist pioglitazone underwent a clinical revival, especially based on the IRIS (Insulin Resistance Intervention After Stroke) study, a randomized controlled trial in 3,876 patients without diabetes status post–transient ischemic attack/ischemic stroke who were clinically followed for 4.8 years. We discuss preclinical basic translational findings and randomized controlled trials related to the beneficial and adverse effects of PPARg agonists of the thiazolidinedione class, with a particular focus on the last 5 years. The objective is a data-driven approach to set the preclinical and clinical study record straight. The convincing recent clinical trial data on the lack of significant toxicity in high-risk populations justify the timely conduct of clinical studies to achieve “repurposing” or “repositioning” of pioglitazone for the treatment of clinical PAH.
AB - Translational research is essential to the development of reverse-remodeling strategies for the treatment of pulmonary vascular disease, pulmonary hypertension, and heart failure via mechanistic in vivo studies using animal models resembling human pulmonary arterial hypertension (PAH), cardiovascular remodeling, and progressive right heart failure. Since 2007, peroxisome proliferator–activated receptor g (PPARg) agonists have emerged as promising novel, antiproliferative, antiinflammatory, insulin-sensitizing, efficient medications for the treatment of PAH. However, early diabetes study results, their subsequent misinterpretations, errors in published review articles, and rumors regarding potential adverse effects in the literature have dampened enthusiasm for considering pharmacological PPARg activation for the treatment of cardiovascular diseases, including PAH. Most recently, the thiazolidinedione class PPARg agonist pioglitazone underwent a clinical revival, especially based on the IRIS (Insulin Resistance Intervention After Stroke) study, a randomized controlled trial in 3,876 patients without diabetes status post–transient ischemic attack/ischemic stroke who were clinically followed for 4.8 years. We discuss preclinical basic translational findings and randomized controlled trials related to the beneficial and adverse effects of PPARg agonists of the thiazolidinedione class, with a particular focus on the last 5 years. The objective is a data-driven approach to set the preclinical and clinical study record straight. The convincing recent clinical trial data on the lack of significant toxicity in high-risk populations justify the timely conduct of clinical studies to achieve “repurposing” or “repositioning” of pioglitazone for the treatment of clinical PAH.
KW - Metabolism
KW - Peroxisome proliferator–activated receptor
KW - Pioglitazone
KW - Pulmonary hypertension
KW - Repurposing drugs
UR - http://www.scopus.com/inward/record.url?scp=85078816927&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85078816927&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2019-0226PS
DO - 10.1165/rcmb.2019-0226PS
M3 - Review article
C2 - 31577451
AN - SCOPUS:85078816927
VL - 62
SP - 143
EP - 156
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
SN - 1044-1549
IS - 2
ER -