The role of inflammatory pathway activation and elevation of serum inflammatory cytokines in age-related disease states, frailty, and functional decline is an active area of investigation (Singh and Newman, 2011
; Chen and Frangogiannis, 2010
). Chronic activation of NF-kB induced inflammatory cascades, such as that induced via deletion of IL-10, influences the frailty phenotype and the associated vulnerability to multi-systemic decline in these mice, similar to that observed in frail older human adults (Hanada and Yoshimura, 2002
; Kuhn et al., 1993
; Rennick et al., 1995
; Lira et al., 2012
). These conditions include hypertension, congestive heart failure, metabolic and endocrine abnormalities, among other conditions (Kassan et al., 2011
; Barzilay et al., 2007
; Newman et al., 2001
). Our efforts in this paper were, in part, meant to determine whether the loss of IL-10 influences the cardiovascular pathophysiology observed in frailty and in aging, and help to determine if these changes may be a potential target for modifying age-related cardiovascular mortality and morbidity.
This study has established a relation between the loss of IL-10 and associated age related cardiovascular dysfunction. The inability of the aortas of old IL-10(tm/tm) mice to relax with muscarinic stimulation can be attributed to endothelial dysfunction. We also observed an increased blood pressure and vascular stiffness in old IL-10(tm/tm) as compared to age matched WT mice. Additionally, the hearts of the old IL-10(tm/tm) mice also undergo dynamic changes causing asymmetric hypertrophy, and both systolic and diastolic dysfunction.
Our data suggest that the vascular endothelial dysfunction and stiffness may potentially be important in the development of early mortality observed in the frail mouse (Ko et al., 2012
). With IL-10(tm/tm), we observed that cholinergic agonists cause vasoconstriction in mice aortas despite the fact that all pathways of endothelial dependent relaxation are not inhibited. It is not clear whether this is caused specifically by a lack of IL-10 or due more generally to the activation of chronic inflammatory pathways. Interestingly, however, we demonstrated that this impaired endothelial vasorelaxation is reversible with both COX inhibitors and TXA2
The unchecked activation of endothelium causes activation of multiple signaling cascades. This especially includes the eicosanoids, the signaling molecules produced by the substrate arachidonic acid, specifically via prostaglandin H2
) synthase (COX1/2 and peroxidase) (Gryglewski, 2008
). These enzymes are committed to production of prostaglandins, prostacyclin and thromboxane. Different cell types convert PGH2
to different end products, which may also depend on the cell stress and conditions. The peroxidase in PGH2
synthase can produce peroxide, which oxidizes heme iron. The resulting heme is capable of accepting electron from tyrosine residue (385) and hence the resulting tyrosine residue is supposed to extract a hydrogen atom from arachidonic acid to produce reactive oxygen species (Shimokawa et al., 1990
). On the other hand, vascular endothelial cells express both isoforms of COX, COX-1 (constitutive) and COX-2 (inducible), which produce PGH2
, a substrate for both PGI2
(Marnett et al., 1999
; Smith et al., 1996
). While PGI2
causes vasorelaxation, TXA2
causes vasoconstriction (Bunting et al., 1983
). Indeed, it is interesting to consider the potential beneficial effect of COX inhibitors in endothelial protection as we age.
We consider IL-10 to be more than just the cytokine synthesis inhibitory factor; it might very well also contain and check the unregulated production of eicosanoids and their activation in response to local inflammatory processes such as in infection, systemic conditions like sepsis and chronic inflammatory processes such as aging. The frail and immune compromised phenotypes of IL-10(tm/tm) mouse model reinforce the same. Unexpressed under most normal conditions and inducible under inflammatory stress, COX-2 is known to be nitrosylated and activated via iNOS (Kim et al., 2005
), and IL-10 decreases TNF and iNOS production (Bosschaerts et al., 2011
). Hence, IL-10 could have the ability to suppress the activity of COX by checking NOS activation. Indeed, our study also suggests that in youth the abundance of iNOS mRNA is 2 fold higher in the aortic tissue of IL-10 depleted mice as compared to WT controls. Similarly, this iNOS induction is possibly able to drive the abundance of COX2 mRNA, which is also significantly higher in young IL-10(tm/tm) mouse aorta as compared to WT counterparts. Interestingly, the abundance of COX2 and iNOS was not different in old IL-10(tm/tm) and WT mice aortas. This may be due to differences in protein synthesis, post-translational modification or degradation. Moreover, it is known that both iNOS and COX2 are regulated via NF-kB (Baeuerle and Baltimore, 1996
) and its role in IL-10(tm/tm) mouse model needs to be elucidated. Previous research suggests that in a few studies IL-10 levels have been inversely correlated with cardiovascular morbidity and mortality in a population suffering with myocardial infarction, stroke, acute coronary syndrome and atherosclerosis (Heeschen et al., 2003
; Cavusoglu et al., 2011
; Caligiuri et al., 2003
; Mallat et al., 1999
; Pinderski Oslund et al., 1999
Here we demonstrate a significantly greater increase in blood pressure and vascular stiffness in aging IL-10(tm/tm) mice as compared to WT mice. Thus, it is possible that the loss of compliance may not be a direct effect of IL-10 depletion but an effect of rise in blood pressure caused by endothelial dysfunction. A pressure independent integral of stiffness needs to be studied in order to resolve this question.
IL-10(tm/tm) mice undergo early cardiac remodeling and have impaired function. The fact that the septum gains more mass than the posterior wall represents asymmetric hypertrophy and raises a new question as to what could be the cause of this phenomenon.
Our data, along with proposed mechanisms and the available literature, should open avenues in which IL-10 can be studied in accordance with prostanoids, not only to predict age related cardiovascular changes, but also to modify and therapeutically target cardiovascular syndromes such as age-related systolic hypertension and non-systolic heart failure.