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Targeting NOX in heart failure with preserved ejection fraction

English title Targeting NOX in heart failure with preserved ejection fraction
Applicant Kuster Gabriela
Number 144208
Funding scheme Project funding (Div. I-III)
Research institution Klinik für Kardiologie Bereich Medizin Universitätsspital Basel
Institution of higher education University of Basel - BS
Main discipline Cardiovascular Research
Start/End 01.01.2013 - 31.12.2015
Approved amount 331'800.00
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Keywords (6)

Hypertension; Diastolic Function; Diabetes; Heart Failure; Oxidative Stress; NOX

Lay Summary (German)

Lead
Herzschwäche ist eine häufige Erkrankung, die mit einer hohen Morbidität und Mortalität einhergeht. Bei etwa der Hälfte der Patienten mit Herzschwäche findet sich eine Einschränkung der Pumpfunktion (systolische Funktionsstörung). Bei den übrigen führt eine Störung der Ventrikelrelaxation und -füllung (diastolische Funktionsstörung) zur sogenannten “Herzschwäche mit erhaltener Pumpfunktion (HFPEF)”. Deren Ursachen sind nur unvollständig geklärt und evidenz-basierte Therapie-Richtlinien fehlen.
Lay summary

Inhalt und Ziel des Forschungsprojektes: Ein überdurchschnittlich grosser Anteil der HFPEF Patienten leiden an Bluthochdruck und Diabetes, und diastolische Funktionsstörungen werden bei beiden Erkrankungen beobachtet. Pathophysiologisch werden multiple Veränderungen sowohl der extrazellulären Matrix als auch der Kardiomyozyten als Ursache diskutiert.

NADPH Oxidasen (NOX) sind Transmembran-Proteine, welche Sauerstoff-Radikale (ROS) produzieren, die an der myokardialen Fibrosierung, der Zellhypertrophie und Störungen des Calciumstoffwechsels beteiligt sind und somit zur diastolischen Funktionsstörung beitragen können. Im Herzen wurden bis anhin die Isoformen NOX2 und 4, sowie kürzlich NOX1 nachgewiesen. Während die Rollen von NOX2 und 4 im Herzen bereits untersucht worden sind, ist die Funktion von NOX1 noch weitgehend unbekannt.

Erste Untersuchungen aus unserem Labor zeigen, dass NOX1 in Kardiomyozyten als Antwort auf neurohumoralen und metabolischen Stress hochreguliert wird und zu ROS-Freisetzung und Zelltod beiträgt. Im vorliegenden Forschungsprojekt prüfen wir anhand von Zellkultur- und Tiermodellen die Hypothese, dass NOX1 am myokardialen Umbau und der diastolischen Funktionsstörung bei hypertensiver und metabolischer Herzerkrankung beteiligt ist und somit eine Rolle in der Entstehung der HFPEF spielt.

Relevanz: Erkenntnisse aus diesen Untersuchungen werden neue Einblicke in die Pathogenese der HFPEF ermöglichen. Solche Erkenntnisse sind für die Entwicklung neuer Strategien zur Prävention und Behandlung der diastolischen Dysfunktion und Herzschwäche mit erhaltener Pumpfunktion von Bedeutung.


Direct link to Lay Summary Last update: 11.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Polo-Like Kinase 2 is Dynamically Regulated to Coordinate Proliferation and Early Lineage Specification Downstream of Yes-Associated Protein 1 in Cardiac Progenitor Cells.
Mochizuki Michika, Lorenz Vera, Ivanek Robert, Della Verde Giacomo, Gaudiello Emanuele, Marsano Anna, Pfister Otmar, Kuster Gabriela M (2017), Polo-Like Kinase 2 is Dynamically Regulated to Coordinate Proliferation and Early Lineage Specification Downstream of Yes-Associated Protein 1 in Cardiac Progenitor Cells., in Journal of the American Heart Association, 6(10), e005920.
Noninvasive Contrast-Enhanced Ultrasound Molecular Imaging Detects Myocardial Inflammatory Response in Autoimmune Myocarditis.
Steinl David C, Xu Lifen, Khanicheh Elham, Ellertsdottir Elin, Ochoa-Espinosa Amanda, Mitterhuber Martina, Glatz Katharina, Kuster Gabriela M, Kaufmann Beat A (2016), Noninvasive Contrast-Enhanced Ultrasound Molecular Imaging Detects Myocardial Inflammatory Response in Autoimmune Myocarditis., in Circulation. Cardiovascular imaging, 9(8), e004720.
Molecular imaging reveals rapid reduction of endothelial activation in early atherosclerosis with apocynin independent of antioxidative properties.
Khanicheh Elham, Qi Yue, Xie Aris, Mitterhuber Martina, Xu Lifen, Mochizuki Michika, Daali Youssef, Jaquet Vincent, Krause Karl-Heinz, Ruggeri Zaverio M, Kuster Gabriela M, Lindner Jonathan R, Kaufmann Beat A (2013), Molecular imaging reveals rapid reduction of endothelial activation in early atherosclerosis with apocynin independent of antioxidative properties., in Arteriosclerosis, thrombosis, and vascular biology, 33(9), 2187-92.

Collaboration

Group / person Country
Types of collaboration
PD Dr. med. B.A. Kaufmann, Department of Biomedicine, Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof. K.H. Krause, Geneva University Hospitals, Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
6th Cardiovascular and Metabolic Research Conference Poster NOX-1 participates in mouse cardiac remodeling under high fat high sugar diet. 19.01.2017 Fribourg, Switzerland Kuster Gabriela; Lorenz Vera;
Annual Assembly of the Swiss Society of Cardiology 2015 Talk given at a conference Translational Research in Cardiology: Maybe Clinical Reality Tomorrow 11.06.2015 Zurich, Switzerland Kuster Gabriela;
EMBO Conference on Stem Cells in Cancer and Regenerative Medicine Poster LN inhibits cardiac progenitor cell cycle via non-canonical Hippo/YAP signaling. 12.10.2014 Heidelberg, Germany Lorenz Vera; Kuster Gabriela;
Heart Failure Congress of the European Society of Cardiology Heart Failure Association Talk given at a conference Disruption of endogenous Flt3-signaling leads to depletion of cardiac side population progenitor cells and subclinical cardiomyopathy. 17.05.2014 Athens, Greece Lorenz Vera; Kuster Gabriela;
3rd Cardiovascular and Metabolic Research Conference Talk given at a conference Absence of FL is associated with enhanced cell cycle activity of CPCs. 16.01.2014 Fribourg, Switzerland Lorenz Vera; Kuster Gabriela;
2nd Cardiovascular and Metabolic Research Conference Poster LN induces cell cycle withdrawal of CPCs and myoblasts involving regulation of the Hippo/YAP pathway. 10.01.2013 Berne, Switzerland Kuster Gabriela; Lorenz Vera;


Associated projects

Number Title Start Funding scheme
128782 R'equip grant for Visual Sonics Vevo 770 high resolution small animal ultrasound system 01.12.2009 R'EQUIP
111353 Role of reactive oxygen species in the regulation of beta-1-integrin expression and function in cardiomyocytes (zu Score) 01.09.2006 Project funding (Div. I-III)

Abstract

Heart failure (HF) with preserved ejection fraction (EF) (HFPEF) has emerged as a distinct disease entity that accounts for roughly half of all HF cases. Diagnostic criteria of HFPEF include clinical signs or symptoms of HF and echocardiographic evidence of normal left ventricular systolic but abnormal diastolic function. Prevalence of hypertension and diabetes is high among patients with HFPEF and both conditions are associated with diastolic dysfunction. Whereas survival improved in patients with HF with reduced EF due to recent advances in therapy, mortality remained high in HFPEF as neurohumoral inhibitors failed to improve outcome in these patients. Understanding of the pathophysiology of HFPEF is still vague and evidence-based guidelines for treatment of diastolic dysfunction and HFPEF are lacking. Potential mechanisms of the left ventricular diastolic dysfunction underlying HFPEF integrate abnormalities of the extracellular matrix, the cardiomyocytes (CMC) and their myofilamentary proteins. Oxidative stress is an important factor in these processes and reactive oxygen species (ROS) originating from NADPH oxidase (NOX) have been implicated in myocardial fibrosis, hypertrophy and impaired calcium handling associated with diastolic dysfunction. NOX are transmembrane proteins dedicated to the production of ROS and NOX2, 4 as well as recently NOX1 have been identified in the heart. Whereas NOX2 and 4 contribute to cardiac hypertrophy and fibrosis, NOX1 has been implicated in blood pressure regulation and vascular remodeling. However, the role of NOX1 in cardiac remodeling has not been investigated. Preliminary data from our laboratory demonstrate significant regulation of NOX1 in CMC in response to high glucose (HG) and neurohormonal stimulation, as well as marked contribution of NOX1 to HG-induced NOX activity and CMC apoptosis, prompting us to hypothesize that NOX1 is involved in cardiac remodeling in metabolic and hypertensive heart disease (HHD), which are both associated with diastolic dysfunction/failure. Therefore, the overall goal of this study is to define the role of NOX1 in the pathophysiology of diastolic dysfunction and HFPEF. Specific Aim 1. To test the hypothesis that NOX1 contributes to cardiac remodeling in HHD associated with diastolic dysfunction and HFPEF. Mice will be inserted micro-osmotic minipumps for s.c. release of angiotensin II for up to four weeks and the role of NOX1 will be examined using NOX1-/y mice, myocardial shRNA injection and pharmacological inhibition. Cardiac morphology and function will be assessed by echocardiography as well as immunohistochemistry and molecular tissue analyses at the time of termination.Specific Aim 2. To test the hypothesis that NOX1 contributes to metabolic/type II diabetic cardiac remodeling associated with diastolic dysfunction and HFPEF in a mouse model of western diet. NOX1-/y and wt mice will be fed a high fat/high sugar diet to induce metabolic syndrome/type II diabetes. After eight months, cardiac morphology and function will be assessed as outlined above. Specific Aim 3. To define NOX regulation and identify the molecular mechanisms underlying NOX- mediated hypertrophic and hyperglycemic CMC remodeling in vitro. Complementary in vitro experiments will be performed in normal and siRNA-mediated NOX1-, 2- or 4-silenced rat CMC to assess and identify mechanisms of regulated NOX expression and NOX-isoform-dependent signaling in hypertrophic and hyperglycemic CMC remodeling.Significance and Outlook: NOX-derived ROS have been shown to mediate important features relevant to diastolic dysfunction and HFPEF. Improved pathophysiological understanding of HFPEF and of the roles of different NOX isoforms is mandatory to develop novel therapeutic strategies that may consist of the isoform-specific inhibition of NOX for prevention and treatment of HFPEF in the future.
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