Published Online
on March 5, 2007

A more recent version of this article appeared on March 13, 2007

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Submitted on September 8, 2006
Accepted on December 29, 2006

Pulmonary Arterial Hypertension Is Linked to Insulin Resistance and Reversed by Peroxisome Proliferator-Activated Receptor- Activation

Georg Hansmann MD, Roger A. Wagner MD, PhD, Stefan Schellong BA, Vinicio A. de Jesus Perez MD, Takashi Urashima MD, Lingli Wang MD, Ahmad Y. Sheikh MD, Renée S. Suen BSc, Duncan J. Stewart MD, and Marlene Rabinovitch MD^*

From the Department of Pediatrics, Division of Pediatric Cardiology (G.H., S.S., V.A.D.J.P., T.U., L.W., M.R.), Department of Medicine, Division of Cardiovascular Medicine (R.A.W.), and Department of Cardiovascular Surgery (A.Y.S.), Stanford University School of Medicine, Stanford, Calif, and Department of Medicine, Division of Cardiology, University of Toronto, Toronto, Ontario, Canada (R.S.S., D.J.S.).

^* To whom correspondence should be addressed. E-mail: marlener{at}stanford.edu.

Background--Patients with pulmonary arterial hypertension (PAH) have reduced expression of apolipoprotein E (apoE) and peroxisome proliferator-activated receptor- 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- agonist (eg, rosiglitazone).

Methods and 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- activation can reverse PAH in an animal model.

Key words: apolipoproteins • glucose • hypercholesterolemia • hypertension, pulmonary • insulin • metabolism • PPAR gamma

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