Abstract 17957: Obesity From Leptin Receptor Deficiency Provides Resistance to the Development of Pulmonary Hypertension
Introduction: Pulmonary arterial hypertension (PAH) is a proliferative vascular disease characterized by mitochondrial suppression in the pulmonary artery and right ventricle (RV), but also other systemic tissues, similar to what is seen in metabolic syndrome and obesity. Some studies suggest that obesity may paradoxically be a protective factor in PAH, similar to what has been shown in congestive heart failure (i.e. the obesity paradox).
Hypothesis: As leptin receptor polymorphisms, hyperleptinemia, and leptin resistance are associated with obesity, we hypothesized that obese, leptin receptor deficient rats (JCR:LA-cp rats) would be protected from developing pharmacologically induced PAH by monocrotaline (MCT), a standard PAH model.
Methods: Obese JCR:LA-cp rats were given intraperitoneal injections of MCT (n=6) vs. vehicle (n=6) and compared to lean JCR rats (n=6 MCT and n=6 vehicle). After three weeks, hemodynamics were assessed using echocardiography and right heart catheterizations. Lung histology was assessed with hematoxylin and eosin staining.
Results: Leptin receptor deficient rats were more obese than lean controls (weighing 528 ± 8g versus 343 ± 4g). In lean controls (normal leptin receptor), MCT increased RV systolic pressure (RVSP) compared to vehicle (43.0 ± 3.5mmHg vs. 26.2 ± 0.7mmHg, p<0.01), and increased RV mass (221 ± 19mg vs. 161 ± 9mg). Furthermore, cardiac output was reduced in MCT lean rats compared to vehicle (120.8 ± 7.5μL/min vs. 84.2 ± 9.7μL/min, p<0.05). However in obese, leptin receptor deficient rats, MCT did not increase RVSP vs. vehicle (33.5 ± 4.1mmHg vs. 30.2 ± 1.3mmHg) or RV mass, and cardiac output was unchanged. On lung histology, the average percent medial wall thickness of small pulmonary arteries was increased by MCT in lean rats (52.0 ± 1.5% in MCT vs. 39.6 ± 2.4% in vehicle, p<0.05), but unchanged in obese rats.
Conclusions: Obese leptin receptor deficient rats are resistant to MCT induced PAH indicating that leptin downstream signaling may contribute to pulmonary vascular and RV remodeling. Impaired leptin signaling in obesity may explain the “obesity paradox” of PAH, revealing a novel pathway that could be therapeutically targeted in PAH.
Author Disclosures: V. Gurtu: None. A. Kinnaird: None. S. Proctor: None. G. Sutendra: None. E. Michelakis: None.
- © 2016 by American Heart Association, Inc.