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 phenotype and its susceptibility to injury are far from being fully understood. Although previous literature reports a role of the mitochondrial enzyme arginase-II (Arg-II) in development of heart failure, contradictory results are reported and no systematic analysis of cellular expression and localization of Arg-II in the heart has been performed. Whether and how Arg-II participates in cardiac aging are still unknown. In this study, we demonstrate, to our surprise, that Arg-II is not expressed in cardiomyocytes from aged mice and human patients, but upregulated in non-myocytes of the aging heart, including macrophages, fibroblasts, endothelial cells. Mice with genetic deficiency of arg-ii ( arg-ii -/- ) 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 Arg-II mediates IL-1β release from macrophages of old mice, contributing to the above-described cardiac aging phenotype. In addition, Arg-II 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 Arg-II on cardiomyocytes, fibroblasts, and endothelial cells mediated by IL-1β from aging macrophages as well as a cell-autonomous effect of Arg-II through mtROS in fibroblasts contributing to cardiac aging phenotype. 

Cell-autonomous and non-cell-autonomous effects of arginase-II 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 phenotype and its susceptibility to injury are far from being fully understood. Although previous literature reports a role of the mitochondrial enzyme arginase-II (Arg-II) in development of heart failure, contradictory results are reported and no systematic analysis of cellular expression and localization of Arg-II in the heart has been performed. Whether and how Arg-II participates in cardiac aging are still unknown. In this study, we demonstrate, to our surprise, that Arg-II is not expressed in cardiomyocytes from aged mice and human patients, but upregulated in non-myocytes of the aging heart, including macrophages, fibroblasts, endothelial cells. Mice with genetic deficiency of arg-ii (arg-ii-/-) 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 Arg-II mediates IL-1β release from macrophages of old mice, contributing to the above-described cardiac aging phenotype. In addition, Arg-II 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 Arg-II on cardiomyocytes, fibroblasts, and endothelial cells mediated by IL-1β from aging macrophages as well as a cell-autonomous effect of Arg-II through mtROS in fibroblasts contributing to cardiac aging phenotype.

BACKGROUND Fibrous capsules (Fb) in response to cardiovascular implantable electronic devices (CIEDs), including a pacemaker (P) system, can produce patient discomfort and difficulties in revision surgery due partially to their increased compressive strength, previously linked to elevated tissue fibers. OBJECTIVE To quantify structural proteins, determine if biologic extracellular matrix-enveloped CIEDs (PECM) caused differential Fb properties, and to implement a realistic mechanical model. METHODS Retrieved Fb (-P and -PECM) from minipigs were subjected to biomechanical (shear oscillation and uniaxial compression) and histological (collagen I and elastin) analyses. RESULTS Fb-PECM showed significant decreases compared to Fb-P in: low strain-loss modulus (390 vs. 541 Pa) across angular frequencies, high strain-compressive elastic modulus (1043 vs. 2042 kPa), and elastic fiber content (1.92 vs. 3.15 μg/mg tissue). Decreases in elastin were particularly noted closer to the implant’s surface (Fb-PECM = 71% vs. Fb-P = 143% relative to dermal elastin at mid-tangential sections) and verified with a solid mechanics hyperelasticity with direction-dependent fiber viscoelasticity compression simulation (r2 ≥ 98.9%). CONCLUSIONS The biologic envelope composed of decellularized porcine small intestine submucosa ECM for CIEDs promoted fibrous tissues with less elastic fibers. Novel compression modeling analyses directly correlated this singular reduction to more desirable subcutaneous tissue mechanics.

/pdf/reduced-fibrous-capsule-elastic-fibers-from-biologic-ecm-1al8rvrb.pdf

Reduced fibrous capsule elastic fibers from biologic ECM-enveloped CIEDs in minipigs, supported with a novel compression mechanics model

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Reduced fibrous capsule elastic fibers from biologic ECM-enveloped CIEDs in minipigs, supported with a novel compression mechanics model