Guanghong Jia1, Javad Habibi2, Annayya R Aroor2, Michael A Hill3, Vincent G DeMarco4, Li E Lee5, Lixin Ma5, Brady J Barron2, Adam Whaley-Connell2, James R Sowers6. 1. Diabetes and Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, MO 65212, USA; Research Service, Harry S Truman Memorial Veterans Hospital, 800 Hospital Dr, Columbia, MO 65201, USA. Electronic address: Jiag@health.missouri.edu. 2. Diabetes and Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, MO 65212, USA; Research Service, Harry S Truman Memorial Veterans Hospital, 800 Hospital Dr, Columbia, MO 65201, USA. 3. Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO 65212, USA; Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65212, USA. 4. Diabetes and Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, MO 65212, USA; Research Service, Harry S Truman Memorial Veterans Hospital, 800 Hospital Dr, Columbia, MO 65201, USA; Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO 65212, USA. 5. Research Service, Harry S Truman Memorial Veterans Hospital, 800 Hospital Dr, Columbia, MO 65201, USA; Department of Radiology, University of Missouri school of Medicine, Columbia, MO 65212, USA. 6. Diabetes and Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, MO 65212, USA; Research Service, Harry S Truman Memorial Veterans Hospital, 800 Hospital Dr, Columbia, MO 65201, USA; Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO 65212, USA; Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65212, USA. Electronic address: Sowersj@health.missouri.edu.
Abstract
OBJECTIVE: Enhanced activation of cell specific mineralocorticoid receptors (MRs) in obesity plays a key role in the development of cardiovascular disease including cardiac diastolic dysfunction as a critical prognosticator. Our previous investigations demonstrated that selective endothelium MR activation promotes a maladaptive inflammatory response and fibrosis in cardiovascular tissue in female mice fed a western diet (WD), and this was associated with expression and activation of the epithelial sodium channel on the surface of endothelial cells (EnNaC). However, the specific role of EnNaC signaling in the development of cardiac stiffness and diastolic dysfunction has not been examined. We hypothesized that targeted inhibition of EnNaC with low dose amiloride would prevent WD-induced diastolic dysfunction by suppressing abnormal endothelial permeability, inflammation and oxidative stress, and myocardial fibrosis. MATERIALS/ METHODS: Four week-old female C57BL6/J mice were fed a WD with or without a low dose of amiloride (1mg/kg/day) for 16weeks. Left ventricular cardiac function was evaluated by magnetic resonance imaging. In addition, we examined coronary vessel and cardiac remodeling, fibrosis, macrophage infiltration using immunohistochemistry, western blot and real time PCR. RESULTS: Amiloride, an antagonist of EnNaC, attenuated WD-induced impairment of left ventricular initial filling rate and relaxation time. Cardiac diastolic dysfunction was associated with increases in coronary endothelium remodeling and permeability that paralleled WD-induced increases in F-actin and fibronectin, decreased expression of claudin-5 and occludin, and increased macrophage recruitment, M1 polarization, cardiac oxidative stress, fibrosis and maladaptive remodeling. CONCLUSION: Our data support the concept that EnNaC activation mediates endothelium permeability which, in turn, promotes macrophage infiltration, M1 polarization, and oxidative stress, resulting in cardiac fibrosis and diastolic dysfunction in females with diet induced obesity.
OBJECTIVE: Enhanced activation of cell specific mineralocorticoid receptors (MRs) in obesity plays a key role in the development of cardiovascular disease including cardiac diastolic dysfunction as a critical prognosticator. Our previous investigations demonstrated that selective endothelium MR activation promotes a maladaptive inflammatory response and fibrosis in cardiovascular tissue in female mice fed a western diet (WD), and this was associated with expression and activation of the epithelial sodium channel on the surface of endothelial cells (EnNaC). However, the specific role of EnNaC signaling in the development of cardiac stiffness and diastolic dysfunction has not been examined. We hypothesized that targeted inhibition of EnNaC with low dose amiloride would prevent WD-induced diastolic dysfunction by suppressing abnormal endothelial permeability, inflammation and oxidative stress, and myocardial fibrosis. MATERIALS/ METHODS: Four week-old female C57BL6/J mice were fed a WD with or without a low dose of amiloride (1mg/kg/day) for 16weeks. Left ventricular cardiac function was evaluated by magnetic resonance imaging. In addition, we examined coronary vessel and cardiac remodeling, fibrosis, macrophage infiltration using immunohistochemistry, western blot and real time PCR. RESULTS:Amiloride, an antagonist of EnNaC, attenuated WD-induced impairment of left ventricular initial filling rate and relaxation time. Cardiac diastolic dysfunction was associated with increases in coronary endothelium remodeling and permeability that paralleled WD-induced increases in F-actin and fibronectin, decreased expression of claudin-5 and occludin, and increased macrophage recruitment, M1 polarization, cardiac oxidative stress, fibrosis and maladaptive remodeling. CONCLUSION: Our data support the concept that EnNaC activation mediates endothelium permeability which, in turn, promotes macrophage infiltration, M1 polarization, and oxidative stress, resulting in cardiac fibrosis and diastolic dysfunction in females with diet induced obesity.
Authors: Ana Paula Davel; Iris Z Jaffe; Rita C Tostes; Frederic Jaisser; Eric J Belin de Chantemèle Journal: Am J Physiol Heart Circ Physiol Date: 2018-06-29 Impact factor: 4.733
Authors: James R Sowers; Javad Habibi; Guanghong Jia; Brian Bostick; Camila Manrique-Acevedo; Guido Lastra; Yan Yang; Dongqing Chen; Zhe Sun; Timothy L Domeier; William Durante; Adam T Whaley-Connell; Michael A Hill; Frederic Jaisser; Vincent G DeMarco; Annayya R Aroor Journal: Metabolism Date: 2020-04-07 Impact factor: 8.694
Authors: Guanghong Jia; Javad Habibi; Annayya R Aroor; Michael A Hill; Yan Yang; Adam Whaley-Connell; Frederic Jaisser; James R Sowers Journal: Hypertension Date: 2018-09 Impact factor: 10.190
Authors: James R Sowers; Javad Habibi; Annayya R Aroor; Yan Yang; Guido Lastra; Michael A Hill; Adam Whaley-Connell; Frederic Jaisser; Guanghong Jia Journal: Metabolism Date: 2019-07-11 Impact factor: 8.694
Authors: Yuxin Xiong; Annayya R Aroor; Francisco I Ramirez-Perez; Guanghong Jia; Javad Habibi; Camila Manrique-Acevedo; Guido Lastra; Donqqing Chen; Vincent G DeMarco; Luis A Martinez-Lemus; Michael A Hill; Frederic Jaisser; James R Sowers; Adam Whaley-Connell Journal: Am J Physiol Renal Physiol Date: 2020-04-13