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Apolipoprotein E (ApoE) Deficiency is a Novel Risk Factor for Pulmonary Arterial Hypertension (PAH) Independently of Insulin Resistance

Georg Hansmann


R. A. Wagner

T. Urashima

Marlene Rabinovitch


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Conference: 2010 International PHA Conference and Scientific Sessions

Release Date: 06.24.2010

Presentation Type: Abstracts

Hansmann G1,2, Wagner RA3, Urashima T2, Rabinovitch M2
1. Dept. of Cardiology, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA
2. Divisions of Pediatric Cardiology, Stanford University School of Medicine, Stanford, CA, USA
3. Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA

BACKGROUND. ApoE inhibits PDGF-BB signaling, is downregulated in lungs from PAH patients, and a putative transcriptional target downstream of bone morphogenetic protein receptor II (BMP-RII), i.e., the receptor that is dysfunctional in many forms of PAH. We have previously shown that young adult (15-wk old) apoE deficient (-/-) mice require a "second hit," i.e., insulin resistance (IR) or severe hyperlipidemia that occurs on high fat diet, to develop PAH in room air or enhanced PAH in chronic hypoxia. We hypothesized that normoxic, apoE -/- mice - in the absence of high fat diet and IR - would develop PAH, right ventricular hypertrophy and enhanced peripheral pulmonary artery (PA) muscularization with age.

METHODS.
 Male apoE -/- mice and controls (n=4-8) were fed regular chow for 15 weeks or 1 year. A 1.4F catheter was inserted via the jugular vein for assessment of right ventricular systolic pressure (RVSP) and function (RV dp/dt). Systemic BP, LV fractional shortening and cardiac output (CO) were determined by tail-cuff method and echocardiography. For assessment of right (RVH) and left (LVH) ventricular hypertrophy, we calculated the mass ratios of RV to LV+septum (RV/LV+S), and LV+S/BW. Peripheral PA (PPA) muscularization was determined by PA barium injection, PA morphometry at alveolar wall level and calculation of the ratio: partially and fully muscularized peripheral PA / total number of peripheral PA. Fasting blood glucose, plasma insulin and adiponectin were measured with a glucometer and RIA. We further investigated the effects of BMP-2 (10ng/ml) and the PPARγ agonist rosiglitazone (1μM) on apoE protein expression and secretion by WB, and the growth-inhibitory effect of recombinant apoE (10μg/ml) on PDGF-BB-induced human (H) PASMC proliferation by cell count and MTT assay. Statistics: One-way ANOVA/Bonferroni posthoc test.

RESULTS. 15-wk old apoE -/- mice did not differ from controls in terms of RVSP (23.2±0.6 vs. 20.6±0.8 mmHg), RV/LV+S (0.30±0.01 vs. 0.26±0.01), PPA muscularization (8.1±4.2 vs. 2.3±2.3 %), CO and BP. However, when compared to age-matched controls, 1yr-old apoE -/-
mice developed PAH (RVSP 29.5±1.2 vs. 22.8±0.4 mmHg), RVH (RV/LV+S 0.40±0.06 vs. 0.23±0.03) and increased PPA muscularization (30.9±1.5 vs. 11.3±2.6%; p<0.001) in the
absence of IR, as indicated by similar glucose, insulin and adiponectin levels. RV and LV function, LV/BW, CO, BP and HCT were similar at 1year of age. BMP-2 and rosiglitazone stimulated apoE expression and secretion in HPASMC, and apoE inhibited PDGF-BB-induced HPASMC proliferation.

CONCLUSIONS. ApoE deficiency in itself appears to be a novel risk factor for PAH independently of IR that may be overcome by PPARγ activation and subsequent induction of apoE that blocks PDGF-BB signaling. This underlines the potential of PPARγ agonists in the
future treatment of PAH patients with or without insulin resistance.