PPARgamma activation: a potential treatment for pulmonary hypertension.
The pathobiology of pulmonary arterial hypertension (PAH) involves multiple molecular pathways and environmental modifiers and is characterized by progressive obliteration of pulmonary arterioles, leading to increased pulmonary vascular resistance (PVR), right heart failure, and death in approximately 40 to 60% of patients 5 years after diagnosis. There is emerging evidence that many key genes involved in PAH development are targets of the insulin-sensitizing transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma), and that pharmacological PPARgamma activation would lead to their beneficial induction or repression and subsequent antiproliferative, anti-inflammatory, proapoptotic, and direct vasodilatory effects in the vasculature. PPARgamma acts downstream of bone morphogenetic protein receptor II (BMP-RII), which is the cell surface receptor that is mutated or dysfunctional in many forms of PAH. Because our recent clinical observations indicate that insulin resistance may be an environmental risk factor or disease modifier ("second hit"), we suggest that PPARgamma-activating agents might be beneficial in the future treatment of both insulin-resistant and insulin-sensitive PAH patients with or without BMP-RII mutations.
Hansmann
Georg
G
Department of Cardiology, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA. georg.hansmann@gmail.com
Zamanian
Roham T
RT
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects* / Q000235:genetics; D003299:Cooperative Behavior; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D033183:Interdisciplinary Communication; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D057170:Translational Research, Biomedical; D016896:Treatment Outcome
D000959:Antihypertensive Agents; D007004:Hypoglycemic Agents; D036341:Intercellular Signaling Peptides and Proteins; D047495:PPAR gamma