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

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.

Aging and aging-related diseases: from molecular mechanisms to interventions and treatments

“…231 In addition, several reports have suggested that oxidative stress in cardiomyocytes induces the premature senescence of cardiac stromal cells, increases the recruitment of CCR 2+ monocytes, and eventually contributes to an excessive inflammatory response and cardiac dysfunction. 232 Moreover, several studies have shown that aging-related increases in ROS levels contribute to mitochondrial dysfunction, metabolic imbalance and irreparable cardiomyocyte damage via accumulation of mtDNA damage and mutations, which could lead to HF.…”

Cellular senescence: all roads lead to mitochondria

“…Cardiomyocytes from TgMAO‐A mice show increased telomere dysfunction and markers of cellular senescence, which can be rescued by treatment with antioxidant N‐acetyl cysteine (NAC) [9]. More recently, it was shown that MAO‐A driven cardiomyocyte senescence also induces paracrine senescence to cardiac stromal cells [95].…”

Importance of Mitochondria in Cardiac Pathologies: Focus on Uncoupling Proteins and Monoamine Oxidases

“…The importance of MAO for left ventricular remodeling and heart failure development can be shown in mice with chronic overexpression of MAO-A. Here, reactive oxygen species [ 136 ] and 4-hydroxynonenal concentrations increase, followed by mitochondrial dysfunction [ 181 ], cardiomyocyte hypertrophy, reduced left ventricular function and increased cardiac fibrosis [ 73 ], as well as increased cardiac inflammation [ 182 ] (for review, see [ 134 , 183 ]). When transgenic animals are treated with the antioxidant N-acetyl cysteine part of the above effects can be rescued [ 136 , 184 ].…”