Abstract
Suprarenal aortic clamping during abdominal aortic aneurysm (AAA) repair results in ischemia-reperfusion injury (IRI) in local (i.e. kidney) and distant (i.e. heart) tissue. To investigate perioperative approaches that mitigate IRI-induced tissue damage, Wistar rats underwent suprarenal aortic clamping either alone or in combination with short cycles of ischemic conditioning before and/or after clamping. Serum analysis revealed significant reduction in key biochemical parameters reflecting decreased tissue damage at systemic level and improved renal function in conditioned groups compared to controls (p < 0.05), which was corroborated by histolopathological evaluation. Importantly, the levels of DNA damage, as reflected by the biomarkers 8-oxo-G, γH2AX and pATM were reduced in conditioned versus non-conditioned cases. In this setting, NADPH oxidase, a source of free radicals, decreased in the myocardium of conditioned cases. Of note, administration of 5-HD and 8-SPT blocking key protective signaling routes abrogated the salutary effect of conditioning. To further understand the non-targeted effect of IRI on the heart, it was noted that serum TGF-β1 levels decreased in conditioned groups, whereas this difference was eliminated after 5-HD and 8-SPT administration. Collectively, conditioning strategies reduced both renal and myocardial injury. Additionally, the present study highlights TGF-β1 as an attractive target for manipulation in this context.
Highlights
Suprarenal aortic clamping during abdominal aortic aneurysm (AAA) repair results in ischemiareperfusion injury (IRI) in local and distant tissue
Biochemical analysis in the serum of all groups sacrificed in 24 h and 48 h revealed a significant reduction in the acute phase protein C-Reactive Protein (CRP) in the conditioned groups, indicating lower inflammation (Figs. 1 and 2ai)
Compared to non-conditioned group A, serum CPK, Lactic Acid Dehydrogenase (LDH), SGPT and K+ levels were lower in groups B, C and D reflecting reduced cellular lysis and tissue damage systematically in conditioned cases (Fig. 2aiii)
Summary
Suprarenal aortic clamping during abdominal aortic aneurysm (AAA) repair results in ischemiareperfusion injury (IRI) in local (i.e. kidney) and distant (i.e. heart) tissue. Identifying effective strategies to reduce IRI is imperative To this end, the objective of the current study was to investigate on both local (i.e. kidney) and remote (i.e. heart) organ tissues the following: (a) the effect of different perioperative conditioning strategies (IPre, IPost, and combined IPre and IPost) on tissue integrity by assessing key biochemical and histopathological parameters following suprarenal occusion of the aorta; (b) the impact of each strategy on the formation of modified Guanine at 8-O position (8-oxo-G) and the accumulation of phosphorylated histone H2AX at Serine 139 ( termed γH2AX) -two biomarkers reflecting oxidative DNA damage and the formation of Double Strand Breaks (DSBs), respectively- given that free radicals may cause potentially harmful lesions to DNA, and (c) the effect of blocking two key protective pathways involved in IRI on tissue integrity by administering the nonselective adenosine receptor antagonist 8-(p-Sulfophenyl) theophylline hydrate (8-SPT) and the mitochondrial ATP-sensitive (KATP) potassium channel blocker sodium 5-hydroxydecanoate (5-HD)
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