Does genetic deficiency of Arg2 prevent age-associated cardiac inflammation, fibrosis, and susceptibility to ischemic injury in aged mice?
Genetic deletion of Arg2 protects against age-related cardiac inflammation and fibrosis by reducing macrophage-derived IL-1β and fibroblast mtROS.
Aging is a predominant risk factor for heart disease. Aging heart reveals low-grade chronic inflammation, cell apoptosis, cardiac fibrosis, and increased vulnerability to ischemic injury. The underlying molecular mechanisms responsible for cardiac aging and its susceptibility to injury are not fully understood. Although literature reports a role for mitochondrial Arginase 2 (ARG2) in heart failure, contradictory results are reported. How ARG2 participates in cardiac aging is still unknown. In this study, we demonstrate that Arg2 is not expressed in cardiomyocytes from aged mice and humans but is upregulated in non-myocyte cells, including macrophages, fibroblasts, and endothelial cells. Mice with genetic deficiency of Arg2 ( Arg2 -/- ) are protected from age-associated cardiac inflammation, myocyte apoptosis, interstitial and perivascular fibrosis, endothelial-mesenchymal transition (EndMT), and susceptibility to ischemic injury. Further experiments show that ARG2 mediates IL-1β release from macrophages of old mice, contributing to the cardiac aging phenotype. In addition, ARG2 enhances mitochondrial reactive oxygen species (mtROS) and activates cardiac fibroblasts that is inhibited by inhibition of mtROS. Thus, our study demonstrates a non-cell-autonomous effect of ARG2 on cardiomyocytes, fibroblasts, and endothelial cells mediated by IL-1β from aging macrophages as well as a cell-autonomous effect of ARG2 through mtROS in fibroblasts contributing to cardiac aging phenotype.
Potenza et al. (Tue,) studied this question.