title: Left ventricular diastolic dysfunction in Nrf2 knock out mice is associated with cardiac hypertrophy, decreased expression of SERCA2a, and preserved endothelial function.
abstract: Increased production of reactive oxygen species and failure of the antioxidant defense system are considered to play a central role in the pathogenesis of cardiovascular disease. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key master switch controlling the expression of antioxidant and protective enzymes, and was proposed to participate in protection of vascular and cardiac function. This study was undertaken to analyze cardiac and vascular phenotype of mice lacking Nrf2. We found that Nrf2 knock out (Nrf2 KO) mice have a left ventricular (LV) diastolic dysfunction, characterized by prolonged E wave deceleration time, relaxation time and total diastolic time, increased E/A ratio and myocardial performance index, as assessed by echocardiography. LV dysfunction in Nrf2 KO mice was associated with cardiac hypertrophy, and a downregulation of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) in the myocardium. Accordingly, cardiac relaxation was impaired, as demonstrated by decreased responses to β-adrenergic stimulation by isoproterenol ex vivo, and to the cardiac glycoside ouabain in vivo. Surprisingly, we found that vascular endothelial function and endothelial nitric oxide synthase (eNOS)-mediated vascular responses were fully preserved, blood pressure was decreased, and eNOS was upregulated in the aorta and the heart of Nrf2 KO mice. Taken together, these results show that LV dysfunction in Nrf2 KO mice is mainly associated with cardiac hypertrophy and downregulation of SERCA2a, and is independent from changes in coronary vascular function or systemic hemodynamics, which are preserved by a compensatory upregulation of eNOS. These data provide new insights into how Nrf2 expression/function impacts the cardiovascular system.
authors.affiliation: Cardiovascular Research Laboratory, Division of Cardiology, Pneumology and Angiology, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Erkens
authors.affiliation: Cardiovascular Research Laboratory, Division of Cardiology, Pneumology and Angiology, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Kramer
authors.affiliation: Cardiovascular Research Laboratory, Division of Cardiology, Pneumology and Angiology, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Lückstädt
authors.affiliation: Cardiovascular Research Laboratory, Division of Cardiology, Pneumology and Angiology, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Panknin
authors.affiliation: Cardiovascular Research Laboratory, Division of Cardiology, Pneumology and Angiology, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Lisann
authors.initials: L
authors.lastname: Krause
authors.affiliation: Cardiovascular Research Laboratory, Division of Cardiology, Pneumology and Angiology, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Weidenbach
authors.affiliation: Cardiovascular Research Laboratory, Division of Cardiology, Pneumology and Angiology, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dirzka
authors.affiliation: Cardiovascular Research Laboratory, Division of Cardiology, Pneumology and Angiology, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Krenz
authors.affiliation: Institute for Pharmacology and Toxicology, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Evanthia
authors.initials: E
authors.lastname: Mergia
authors.affiliation: Cardiovascular Research Laboratory, Division of Cardiology, Pneumology and Angiology, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Tatsiana
authors.initials: T
authors.lastname: Suvorava
authors.affiliation: Cardiovascular Research Laboratory, Division of Cardiology, Pneumology and Angiology, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Kelm
authors.affiliation: Cardiovascular Research Laboratory, Division of Cardiology, Pneumology and Angiology, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany. Electronic address: Miriam.Cortese@uni-duesseldorf.de.
authors.forename: Miriam M
authors.initials: MM
authors.lastname: Cortese-Krott
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006332:Cardiomegaly / Q000209:etiology / Q000473:pathology*; D009202:Cardiomyopathies / Q000209:etiology / Q000473:pathology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004452:Echocardiography; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006439:Hemodynamics; D061307:Human Umbilical Vein Endothelial Cells; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000473:pathology*; D020257:Ventricular Remodeling
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: Echocardiography; Flow-mediated dilation; High-resolution ultrasound; Nrf2 KO; Translational research; eNOS