Selective Cardiomyocyte Oxidative Stress Leads to Bystander Senescence of Cardiac Stromal Cells.

Hélène Martini,Marianne Dutaur,Jérôme Roncalli,Sylvain Sayir,Damien Maggiorani,Daniel Cussac,Lise Lefevre,Romain Itier,Angelo Parini,Dimitri J Marsal,Jeanne Mialet-Perez,Victorine Douin-Echinard,Nathalie Pizzinat

doi:10.3390/ijms22052245

Abstract

Accumulation of senescent cells in tissues during normal or accelerated aging has been shown to be detrimental and to favor the outcomes of age-related diseases such as heart failure (HF). We have previously shown that oxidative stress dependent on monoamine oxidase A (MAOA) activity in cardiomyocytes promotes mitochondrial damage, the formation of telomere-associated foci, senescence markers, and triggers systolic cardiac dysfunction in a model of transgenic mice overexpressing MAOA in cardiomyocytes (Tg MAOA). However, the impact of cardiomyocyte oxidative stress on the cardiac microenvironment in vivo is still unclear. Our results showed that systolic cardiac dysfunction in Tg MAOA mice was strongly correlated with oxidative stress induced premature senescence of cardiac stromal cells favoring the recruitment of CCR2+ monocytes and the installation of cardiac inflammation. Understanding the interplay between oxidative stress induced premature senescence and accelerated cardiac dysfunction will help to define new molecular pathways at the crossroad between cardiac dysfunction and accelerated aging, which could contribute to the increased susceptibility of the elderly to HF.

Highlights

Advanced age remains a strong predictor for poor outcomes in patients with chronic or acute heart failure (HF)
Excessive oxidative stress generated by monoamine oxidase A (MAOA) activity overexpressed by cardiomyocytes of transgenic mice overexpressing MAOA in cardiomyocytes (Tg MAOA) mice promotes the installation of systolic dysfunction at three to fourmonth ages (Supplementary Table S1) [9]
In Tg MAOA mice, some diffuse staining was evidenced in cardiomyocytes, albeit a predominant strong staining appeared in the non-cardiomyocyte stromal cell fraction, compared to Ntg mice (Figure 1a,b)

Summary

Introduction

Advanced age remains a strong predictor for poor outcomes in patients with chronic or acute heart failure (HF). Age-related changes in cardiac structure and longer exposure to risk factors may render the elderly more prone to develop cardiovascular diseases. Among these factors, the accumulation of reactive oxygen species (ROS) which mainly originate from mitochondria generates oxidative stress, one mechanism known to promote both cardiac dysfunction and stress-induced premature senescence (SIPS) [1,2]. The aging process is to a large extent related to macromolecular damage by ROS, mostly affecting long-lived postmitotic cells such as cardiomyocytes. The sources of mitochondrial ROS responsible for age-related cardiac dysfunction are still under investigation

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Conclusion