Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation.
BACKGROUND
Patients with pulmonary arterial hypertension (PAH) have reduced expression of apolipoprotein E (apoE) and peroxisome proliferator-activated receptor-gamma in lung tissues, and deficiency of both has been linked to insulin resistance. ApoE deficiency leads to enhanced platelet-derived growth factor signaling, which is important in the pathobiology of PAH. We therefore hypothesized that insulin-resistant apoE-deficient (apoE-/-) mice would develop PAH that could be reversed by a peroxisome proliferator-activated receptor-gamma agonist (eg, rosiglitazone).


RESULTS
We report that apoE-/- mice on a high-fat diet develop PAH as judged by elevated right ventricular systolic pressure. Compared with females, male apoE-/- were insulin resistant, had lower plasma adiponectin, and had higher right ventricular systolic pressure associated with right ventricular hypertrophy and increased peripheral pulmonary artery muscularization. Because male apoE-/- mice were insulin resistant and had more severe PAH than female apoE-/- mice, we treated them with rosiglitazone for 4 and 10 weeks. This treatment resulted in markedly higher plasma adiponectin, improved insulin sensitivity, and complete regression of PAH, right ventricular hypertrophy, and abnormal pulmonary artery muscularization in male apoE-/- mice. We further show that recombinant apoE and adiponectin suppress platelet-derived growth factor-BB-mediated proliferation of pulmonary artery smooth muscle cells harvested from apoE-/- or C57Bl/6 control mice.


CONCLUSIONS
We have shown that insulin resistance, low plasma adiponectin levels, and deficiency of apoE may be risk factors for PAH and that peroxisome proliferator-activated receptor-gamma activation can reverse PAH in an animal model.
Hansmann
Georg
G
Department of Pediatrics, Division of Pediatric Cardiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Wagner
Roger A
RA
Schellong
Stefan
S
Perez
Vinicio A de Jesus
VA
Urashima
Takashi
T
Wang
Lingli
L
Sheikh
Ahmad Y
AY
Suen
Renée S
RS
Stewart
Duncan J
DJ
Rabinovitch
Marlene
M
D052242:Adiponectin / Q000097:blood / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology; D000077214:Becaplermin; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004032:Diet; D004195:Disease Models, Animal; D005260:Female; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D047495:PPAR gamma / Q000187:drug effects / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D012307:Risk Factors; D000077154:Rosiglitazone; D012737:Sex Factors; D045162:Thiazolidinediones / Q000494:pharmacology
D052242:Adiponectin; C499919:Adipoq protein, mouse; D001057:Apolipoproteins E; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000077214:Becaplermin