Cell-autonomous and non-cell-autonomous effects of Arginase 2 on cardiac aging

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 the 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 upregulated in non-myocyte cells, including
macrophages, fibroblasts, 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-1b 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-1b from
aging macrophages as well as a cell-autonomous effect of ARG2 through
mtROS in fibroblasts contributing to cardiac aging phenotype.