Neutralization of interleukin-18 ameliorates ischemia/reperfusion-induced myocardial injury.

Ischemia/reperfusion (I/R) injury is characterized by the induction of oxidative stress and proinflammatory cytokine expression. Recently demonstrating that oxidative stress and TNF-alpha each stimulate interleukin (IL)-18 expression in cardiomyocytes, we hypothesized that I/R also induces IL-18 expression and thus exacerbates inflammation and tissue damage. Neutralization of IL-18 signaling should therefore diminish tissue injury following I/R.

Adiponectin blocks interleukin-18-mediated endothelial cell death via APPL1-dependent AMP-activated protein kinase (AMPK) activation and IKK/NF-kappaB/PTEN suppression.

The adipocyte-derived cytokine adiponectin is known to exert anti-inflammatory and anti-apoptotic effects. In patients with atherosclerotic cardiovascular disease, circulating levels of adiponectin correlate inversely with those of the proinflammatory, proapoptotic cytokine interleukin (IL)-18. The opposing actions of IL-18 and adiponectin on both cell survival and inflammation led us to investigate whether adiponectin signaling antagonizes IL-18-mediated endothelial cell death and to identify the underlying molecular mechanisms.

Age-related increases in oxidatively damaged proteins of mouse kidney mitochondrial electron transport chain complexes.

Mitochondrial dysfunction generates reactive oxygen species (ROS) which damage essential macromolecules. Oxidative modification of proteins, DNA, and lipids has been implicated as a major causal factor in the age-associated decline in tissue function. Mitochondrial electron transport chain complexes I and III are the principal sites of ROS production, and oxidative modifications to the complex subunits inhibit their in vitro activity.

Interleukin-18 knockout mice display maladaptive cardiac hypertrophy in response to pressure overload.

Interleukin (IL)-18 is a cardiotropic proinflammatory cytokine chronically elevated in the serum of patients with cardiac hypertrophy (LVH). The purpose of this study was to examine the role of IL-18 in pressure-overload hypertrophy using wild type (WT) and IL-18 -/- (null) mice. Adult male C57Bl/6 mice underwent transaortic constriction (TAC) for 7days or sham surgery.

Hepatic gene and protein expression of primary components of the IGF-I axis in long lived Snell dwarf mice.

Recent evidence indicates that the GH/IGF-I axis plays a key role in the control of aging and longevity. To better understand this biological relationship we examined the mRNA and corresponding protein levels of primary IGF-I axis genes in the livers of young and aged long-lived Snell dwarf mice relative to their age-matched controls. We demonstrated that the level of IGF-I and ALS mRNAs is dramatically decreased in both young and aged dwarf livers, transcripts encoding IGF-IR and IGFBP-I are elevated in young dwarfs, but normalize to control levels in aged dwarf livers while transcripts encoding IGFBP-3 are elevated only in aged controls.

Altered cholesterologenic and lipogenic transcriptional profile in livers of aging Snell dwarf (Pit1dw/dwJ) mice.

Several murine models demonstrate that mammalian longevity can be increased by single gene mutations affecting endocrine signalling, particularly via the GH/IGF-1 axis. In this study, we identify age-independent patterns of hepatic gene expression characteristic of long-lived Snell (Pit1(dw/dwJ)) dwarf mice. Comparative microarray analysis of young and aged male livers was performed to discover specific genes differentially expressed between Pit1(dw/dwJ) and control mice.

Altered oxidative stress response of the long-lived Snell dwarf mouse.

Several single gene mutations in mice that increase the murine life span have been identified, including the Pit-1 mutation which results in the Snell dwarf (Pit1(dw/dw)), however, the biological mechanism of this life-span extension is still unclear. Based on studies that show oxidative stress plays an important role in the aging process, we hypothesized that the increased longevity seen in Snell dwarf mice may result from a resistance to oxidative stress. We report that Snell dwarf mice respond to oxidative stress induced by 3-NPA differently than their wild type littermates.

Carbonylation of ER chaperone proteins in aged mouse liver.

Progressive accumulation of oxidative damage to macromolecules in aged tissues is thought to contribute to the decline in tissue function characteristic of the aged phenotype. Mitochondria are a major intracellular source of reactive oxygen species (ROS); however, other organelles are also endogenous sources of oxyradicals and oxidants, which can damage macromolecules. We, therefore, sought to examine the relationship between aging and oxidative damage to ER resident proteins, which exist in a strongly oxidizing environment necessary for disulfide bond formation.