Ghrelin protects musculocutaneous tissue from ischemic necrosis by improving microvascular perfusion

Abstract

Persistent ischemia in musculocutaneous tissue may lead to wound breakdown and necrosis. The objective of this experimental study was to analyze, whether the gastric peptide ghrelin prevents musculocutaneous tissue from necrosis and to elucidate underlying mechanisms. Thirty-two C57BL/6 mice equipped with a dorsal skinfold chamber containing ischemic musculocutaneous tissue were allocated to four groups: 1) ghrelin; 2) N(ω)-nitro-l-arginine methyl ester (l-NAME); 3) ghrelin and l-NAME; and 4) control. Microcirculation, inflammation, angiogenesis, and tissue survival were assessed by fluorescence microscopy. Inducible and endothelial nitric oxide synthase (iNOS I and eNOS), vascular endothelial growth factor (VEGF), as well as nuclear factor κB (NF-κB) were assessed by Western blot analysis. Ghrelin-treated animals showed an increased expression of iNOS and eNOS in critically perfused tissue compared with controls. This was associated with arteriolar dilation, increased arteriolar perfusion, and a sustained functional capillary density. Ghrelin further upregulated NF-κB and VEGF and induced angiogenesis. Finally, ghrelin reduced microvascular leukocyte-endothelial cell interactions, apoptosis, and overall tissue necrosis (P < 0.05 vs. control). Inhibition of nitric oxide by l-NAME did not affect the anti-inflammatory and angiogenic action of ghrelin but completely blunted the ghrelin-induced tissue protection by abrogating the arteriolar dilation, the improved capillary perfusion, and the increased tissue survival. Ghrelin prevents critically perfused tissue from ischemic necrosis. Tissue protection is the result of a nitric oxide synthase-mediated improvement of the microcirculation but not due to induction of angiogenesis or attenuation of inflammation. This might represent a promising, noninvasive, and clinically applicable approach to protect musculocutaneous tissue from ischemia.

Ghrelin Gene Products in Acute and Chronic Inflammation

“…However, it has been proposed that in some circumstances and with some cell types, ghrelin may act as a pro-inflammatory peptide inducing, rather than reducing, NF-jB expression and proinflammatory IL-8 secretion (Kwan et al 2010;Rezaeian et al 2012;Sung et al 2011;Zhao et al 2006). Also the vagus nerve seems to play a central role in ghrelin-mediated inhibition of proinflammatory cytokine release (Cheyuo et al 2011;Wu et al 2007aWu et al , 2008Wu et al , 2009 and that anti-inflammatory activity of vagal stimulation is ghrelinmediated (Bansal et al 2012).…”

The Role of Ghrelin in Neuroprotection after Ischemic Brain Injury

“…Ghrelin may protect against necrosis caused by persistent ischemia in musculoskeletal tissues, but it does so by up-regulating iNOS, which, in turn, improves the local microcirculation [63]. There is some evidence ghrelin may be able to encourage cell survival by stimulating autophagy in cardiomyocytes under simulated hypoxic conditions leading to a more efficient removal of damaged organelles and misfolded proteins [64].…”

Endogenous ghrelin's role in hippocampal neuroprotection after global cerebral ischemia: does endogenous ghrelin protect against global stroke?

“…In global cerebral ischemia, as was used in this study, the principal mode of cell death is necrosis (11). A single study has shown that ghrelin can protect against the necrosis that is caused by persistent ischemia in musculoskeletal tissues, but in this case, it does so by upregulating inducible nitric oxide synthase, which in turn, improves the local microcirculation (54). To the best of our knowledge, no study has tested whether ghrelin can directly influence necrotic cell death after cerebral ischemia.…”