Lack of Contribution of p66shc to Pressure Overload-Induced Right Heart Hypertrophy.

Christine Hirschhäuser,Natascha Sommer,Kerstin Boengler,Rainer Schulz,Klaus-Dieter Schlüter,Ralph Schermuly,Hanna Sarah Kutsche,Julia Bornbaum,Azadeh Esfandiary,Norbert Weissmann,Akylbek Sydykov,Rolf Schreckenberg,Annemarie Wolf

doi:10.3390/ijms21249339

Christine Hirschhäuser, Natascha Sommer + Show 11 more

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https://doi.org/10.3390/ijms21249339

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Abstract

The leading cause of death in pulmonary arterial hypertension (PAH) is right ventricular (RV) failure (RVF). Reactive oxygen species (ROS) have been suggested to play a role in the development of RV hypertrophy (RVH) and the transition to RVF. The hydrogen peroxide-generating protein p66shc has been associated with left ventricular (LV) hypertrophy but its role in RVH is unclear. The purpose of this study was to determine whether genetic deletion of p66shc affects the development and/or progression of RVH and RVF in the pulmonary artery banding (PAB) model of RV pressure overload. The impact of p66shc on mitochondrial ROS formation, RV cardiomyocyte function, as well as on RV morphology and function were studied three weeks after PAB or sham operation. PAB in wild type mice did not affect mitochondrial ROS production or RV cardiomyocyte function, but induced RVH and impaired cardiac function. Genetic deletion of p66shc did also not alter basal mitochondrial ROS production or RV cardiomyocyte function, but impaired RV cardiomyocyte shortening was observed following PAB. The development of RVH and RVF following PAB was not affected by p66shc deletion. Thus, our data suggest that p66shc-derived ROS are not involved in the development and progression of RVH or RVF in PAH.

Highlights

Cardiac hypertrophy occurs as a result of a variety of heart diseases, including pulmonary arterial hypertension (PAH)
There is evidence that mitochondrial Reactive oxygen species (ROS) production is decreased in the compensated state of RV hypertrophy (RVH) whereas the transition from RVH to right ventricular failure (RVF) is associated with oxidative stress [33]
In the present study we investigated whether p66shc, which contributes to the development of LV hypertrophy (LVH), plays a role in RVH

Summary

Introduction

Cardiac hypertrophy occurs as a result of a variety of heart diseases, including pulmonary arterial hypertension (PAH). PAH increases right ventricular (RV) afterload, inducing—if prolonged—RV hypertrophy (RVH). Sustained pressure overload progresses into pathological remodeling of the RV, leading to dilation and culminating in right ventricular failure (RVF) [1]. Reactive oxygen species (ROS) and their excessive production (oxidative stress) have been suggested to play a role in RVH and remodeling [2,3]. While smaller amounts of ROS act as signaling molecules and contribute to cardiac hypertrophy, oxidative stress contributes to the transition of adaptive to maladaptive cardiac hypertrophy (maladaptive remodeling) and the development of RVF [4,5,6]

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