Endothelial Nitric Oxide Synthase-Induced Hypertrophy and Vascular Dysfunction Contribute to the Left Ventricular Dysfunction in Caveolin-1−/− Mice

Caveolin-1 (Cav1)−/− mice display impaired development of left ventricular pressure and increased left ventricular wall thickness but no dilated ventricle; these are typical findings in patients with heart failure with preserved ejection fraction (HfpEF). Aiming to clarify if dysfunctional endotheli...

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Bibliographic Details
Published in:Canadian journal of cardiology 2017-12, Vol.33 (12), p.1716-1724
Main Authors: Ebner, Annette, Kuerbis, Nadine, Brandt, Aljoscha, Zatschler, Birgit, Weinert, Sönke, Poitz, David M., Ebner, Bernd, Augstein, Antje, Wunderlich, Carsten, El-Armouche, Ali, Strasser, Ruth H.
Format: Article
Language:English
Subjects:
Animals
Aorta, Thoracic - drug effects
Aorta, Thoracic - physiopathology
Cardiomegaly - chemically induced
Cardiomegaly - complications
Cardiomegaly - diagnosis
Caveolin 1 - deficiency
Disease Models, Animal
Echocardiography
Electrocardiography
Immunoblotting
Mice
Mice, Knockout
Nitric Oxide Synthase Type III - toxicity
Reactive Oxygen Species - metabolism
Vasoconstriction - drug effects
Vasoconstriction - physiology
Ventricular Dysfunction, Left - etiology
Ventricular Dysfunction, Left - metabolism
Ventricular Dysfunction, Left - physiopathology
Ventricular Function, Left - physiology
Ventricular Remodeling
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Summary:Caveolin-1 (Cav1)−/− mice display impaired development of left ventricular pressure and increased left ventricular wall thickness but no dilated ventricle; these are typical findings in patients with heart failure with preserved ejection fraction (HfpEF). Aiming to clarify if dysfunctional endothelial nitric oxide synthase (eNOS) influences cardiomyocyte contractility, cardiac conduction system, or afterload/vascular resistance, we studied Cav1−/−/eNOS−/− mice. Cardiac function was assessed in vivo by pressure-volume-catheterization of the left ventricle, echocardiography and electrocardiography. In addition, isolated tissue experiments were performed to evaluate cardiomyocyte contractility (atria) and vessel morphology and function (aorta). Histology, immunoblotting and quantitative polymerase chain reaction were applied to characterise radical formation and oxidative stress in the heart. Cardiac hypertrophy was completely reversed in Cav1−/−/eNOS−/− mice. The impaired pump function in Cav1−/− mice was significantly improved in Cav1−/−/eNOS−/− mice, but no complete alignment with eNOS−/− controls was achieved, indicating an additional eNOS-independent mechanism contributing to HFpEF in Cav1−/− mice. It is unlikely that frequently occurring arrhythmias contributed to HFpEF in Cav1−/− mice. In contrast, numerous eNOS-dependent and eNOS-independent vascular abnomalities could explain the cardiac phenotypes of Cav1−/− mice. Synergistic effects between eNOS-related cardiac hypertrophy and vascular hypercontractility appear to underlie the left ventricular dysfunction in Cav1−/−mice. These findings provide insights relevant to the poorly understood pathophysiology of HFpEF. Les souris cavéoline-1 (Cav1)−/− présentent une pression ventriculaire gauche anormale et une augmentation de l’épaisseur de la paroi ventriculaire gauche, sans dilatation du ventricule; ces observations sont caractéristiques des patients atteints d’insuffisance cardiaque à fraction d’éjection préservée (ICFEP). Dans le but de déterminer si un dysfonctionnement de l’oxyde nitrique synthase endothéliale (eNOS) exerce une influence sur la contractilité des cardiomyocytes, le système de conduction cardiaque ou la résistance vasculaire/postcharge, nous avons étudié les souris Cav1−/−/eNOS−/−. La fonction cardiaque a été évaluée in vivo par des mesures de la pression et des volumes via cathétérisme du ventricule gauche, échocardiographie et électrocardiographie. De plus, des expériences sur des t
ISSN:0828-282X
1916-7075
DOI:10.1016/j.cjca.2017.09.015