Aging is associated with an increased susceptibility to ischaemic necrosis due to microvascular perfusion failure but not a reduction in ischaemic tolerance

Abstract

In the present study in a murine model of chronic ischaemia, we analysed: (i) whether aging was associated with an increased susceptibility to ischaemic necrosis, and (ii) whether this was based on microvascular dysfunction or reduced ischaemic tolerance. An ischaemic pedicled skin flap was created in the ear of homozygous hairless mice. The animals were assigned to three age groups, including adolescent (2±1 months), adult (10±2 months) and senescent (19±3 months). Microvascular perfusion of the ischaemic flap was assessed over 5 days by intravital microscopy, evaluating FCD (functional capillary density), capillary dilation response and the area of tissue necrosis. Expression of the stress-protein HO (haem oxygenase)-1 was determined by immunohistochemistry and Western blotting. Induction of chronic ischaemia stimulated a significant expression of HO-1 without a significant difference between the three age groups. This was associated with capillary dilation, which, however, was more pronounced in adolescent (10.5±2.8 μm compared with 3.95±0.79 μm at baseline) and adult (12.1±3.1 μm compared with 3.36±0.45 μm at baseline) animals compared with senescent animals (8.5±1.7 μm compared with 3.28±0.69 μm at baseline; P value not significant). In senescent animals, flap creation further resulted in complete cessation of capillary flow in the distal area of the flap (FCD, 0±0 cm/cm2), whereas adult (11.9±13.5 cm/cm2) and, in particular, adolescent animals (58.4±33.6 cm/cm2; P<0.05) were capable of maintaining residual capillary perfusion. The age-associated microcirculatory dysfunction resulted in a significantly increased flap necrosis of 49±8% (P<0.05) and 42±8% (P<0.05) in senescent and adult animals respectively, compared with 31±6% in adolescent mice. Of interest, functional inhibition of HO-1 by SnPP-IX (tin protoporphyrin-IX) in adolescent mice abrogated capillary dilation, decreased functional capillary density and aggravated tissue necrosis comparably with that observed in senescent mice. Thus aging is associated with an increased susceptibility to tissue necrosis, which is due to a loss of vascular reactivity to endogenous HO-1 expression, rather than a reduction in ischaemic tolerance.

A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro

“…25 In contrast, pronounced chemical or genetic inhibition of basal HO-1 levels is associated with increased cell death and tissue necrosis in models of Alzheimer's disease and aging. 26,27 These effects have partly been explained by a lowered antioxidative capacity 28 and cells being more susceptible to damaging agents during HO-1 inhibition, 29 a property that has been used to sensitize cells for cancer therapy. 30 Given that deregulation of HO-1 in HPTECs correlated well with the known toxic effects of the tested compounds in humans, changes in cellular HO-1 might indicate a cellular process to protect from further damage.…”

Oxidative stress response and Nrf2 signaling in aging

“…In contrast, some reported no change or a decrease. For example, HO-1 expression is not changed in the liver of Wistar rat (24 mo vs. 1.3 mo) [162], and the ear skin (20 mo vs. 2 mo) [163], cerebral cortex of mice (23–24 mo vs. 5–6 mo) [164], cochlea (11 mo vs. 3 mo) [165], and macrophages from mice (3,6,18,21 mo) [166]. HO-1 is decreased in the hippocampus (20 mo vs. 2 mo) [167], spinal cord and astrocytes (13 mo vs. 1.5 mo), and aorta of rat (24 mo vs. 3 mo) [159].…”

Pharmacological and Clinical Aspects of Heme Oxygenase

“…Functional inhibition of HO-1 abrogated capillary dilation, decreased functional capillary density, and aggravated tissue necrosis (comparable with that observed in senescent mice). It appears that aging is associated with an increased susceptibility to tissue necrosis, which is due to a loss of vascular reactivity to endogenous HO-1 levels, rather than to a reduction in ischemic tolerance (Harder et al, 2007). Independent of its PPAR␥ activity, ⌬ 12 -PGJ 2 was shown to protect retinal pigment epithelial cells from oxidative stress by elevating GSH and enhancing MAPK activation (Qin et al, 2006).…”