Andreas B Gevaert1, Hadis Shakeri2, Arthur J Leloup2, Cor E Van Hove2, Guido R Y De Meyer2, Christiaan J Vrints2, Katrien Lemmens2, Emeline M Van Craenenbroeck2. 1. From the Research Group Physiopharmacology (A.B.G., H.S., A.J.L., C.E.V.H., G.R.Y.D.M., K.L.), and Research Group Cardiovascular Diseases, Translational Pathophysiological Research (A.B.G., C.E.V.H., C.J.V., K.L., E.M.V.C.), University of Antwerp, Belgium; and Laboratory for Cellular and Molecular Cardiology and Department of Cardiology, Antwerp University Hospital (UZA), Edegem, Belgium (A.B.G., C.J.V., E.M.V.C.). andreas.gevaert@uantwerpen.be. 2. From the Research Group Physiopharmacology (A.B.G., H.S., A.J.L., C.E.V.H., G.R.Y.D.M., K.L.), and Research Group Cardiovascular Diseases, Translational Pathophysiological Research (A.B.G., C.E.V.H., C.J.V., K.L., E.M.V.C.), University of Antwerp, Belgium; and Laboratory for Cellular and Molecular Cardiology and Department of Cardiology, Antwerp University Hospital (UZA), Edegem, Belgium (A.B.G., C.J.V., E.M.V.C.).
Abstract
BACKGROUND: Because of global aging, the prevalence of heart failure with preserved ejection fraction (HFpEF) continues to rise. Although HFpEF pathophysiology remains incompletely understood, endothelial inflammation is stated to play a central role. Cellular senescence is a process of cellular growth arrest linked with aging and inflammation. We used mice with accelerated aging to investigate the role of cellular senescence in HFpEF development. METHODS AND RESULTS: Senescence-accelerated mice (SAM, n=18) and control mice with normal senescence (n=15) were fed normal chow or a high-fat, high-salt diet (WD). Vascular and cardiac function was assessed at 8, 16, and 24 weeks of age. At 24 weeks, both SAM on WD (SAM-WD) and SAM on regular diet displayed endothelial dysfunction, as evidenced by impaired acetylcholine-induced relaxation of aortic segments and reduced basal nitric oxide. At week 24, SAM-WD had developed HFpEF, characterized by diastolic dysfunction, left ventricular hypertrophy, left atrial dilatation, and interstitial fibrosis. Also, exercise capacity was reduced and lung weight increased. Cardiovascular inflammation and senescence were assessed by immunohistochemical and immunofluorescence staining of hearts and aortas. SAM-WD showed increased endothelial inflammation (intercellular adhesion molecule 1 expression) and increased endothelial senescence (acetyl-p53/CD31 costaining). The latter correlated with diastolic function and intercellular adhesion molecule 1 expression. CONCLUSIONS: SAM develop endothelial dysfunction. Adding a high-salt, high-fat diet accelerates endothelial senescence and instigates endothelial inflammation. This coincides with hemodynamic and structural changes typical of HFpEF. Targeting endothelial senescence could be a new therapeutic avenue in HFpEF.
BACKGROUND: Because of global aging, the prevalence of heart failure with preserved ejection fraction (HFpEF) continues to rise. Although HFpEF pathophysiology remains incompletely understood, endothelial inflammation is stated to play a central role. Cellular senescence is a process of cellular growth arrest linked with aging and inflammation. We used mice with accelerated aging to investigate the role of cellular senescence in HFpEF development. METHODS AND RESULTS: Senescence-accelerated mice (SAM, n=18) and control mice with normal senescence (n=15) were fed normal chow or a high-fat, high-salt diet (WD). Vascular and cardiac function was assessed at 8, 16, and 24 weeks of age. At 24 weeks, both SAM on WD (SAM-WD) and SAM on regular diet displayed endothelial dysfunction, as evidenced by impaired acetylcholine-induced relaxation of aortic segments and reduced basal nitric oxide. At week 24, SAM-WD had developed HFpEF, characterized by diastolic dysfunction, left ventricular hypertrophy, left atrial dilatation, and interstitial fibrosis. Also, exercise capacity was reduced and lung weight increased. Cardiovascular inflammation and senescence were assessed by immunohistochemical and immunofluorescence staining of hearts and aortas. SAM-WD showed increased endothelial inflammation (intercellular adhesion molecule 1 expression) and increased endothelial senescence (acetyl-p53/CD31 costaining). The latter correlated with diastolic function and intercellular adhesion molecule 1 expression. CONCLUSIONS: SAM develop endothelial dysfunction. Adding a high-salt, high-fat diet accelerates endothelial senescence and instigates endothelial inflammation. This coincides with hemodynamic and structural changes typical of HFpEF. Targeting endothelial senescence could be a new therapeutic avenue in HFpEF.
Authors: Haobo Li; Margaret H Hastings; James Rhee; Lena E Trager; Jason D Roh; Anthony Rosenzweig Journal: Circ Res Date: 2020-02-13 Impact factor: 17.367
Authors: Kathryn Dryer; Mark Gajjar; Nikhil Narang; Margaret Lee; Jonathan Paul; Atman P Shah; Sandeep Nathan; Javed Butler; Charles J Davidson; William F Fearon; Sanjiv J Shah; John E A Blair Journal: Am J Physiol Heart Circ Physiol Date: 2018-02-09 Impact factor: 4.733