Cytoprotective effects of transgenic neuroglobin overexpression in an acute and chronic mouse model of ischemic heart disease

Abstract

Neuroglobin (NGB) is an oxygen-binding protein that is mainly expressed in nervous tissues where it is considered to be neuroprotective during ischemic brain injury. Interestingly, transgenic mice overexpressing NGB reveal cytoprotective effects on tissues lacking endogenous NGB, which might indicate a therapeutic role for NGB in a broad range of ischemic conditions. In the present study, we investigated the effect of NGB overexpression on survival as well as on the size and occurrence of myocardial infarctions (MI) in a mouse model of acute MI (AMI) and a model of advanced atherosclerosis (ApoE Fbn1 mice), in which coronary plaques and MI develop in mice being fed a Western-type diet. Overexpression of NGB significantly enhanced post-AMI survival and reduced MI size by 14% 1 week after AMI. Gene expression analysis of the infarction border showed reduction of tissue hypoxia and attenuation of hypoxia-induced inflammatory pathways, which might be responsible for these beneficial effects. In contrast, NGB overexpression did not affect survival or occurrence of MI in the atherosclerotic mice although the incidence of coronary plaques was significantly reduced. In conclusion, NGB proved to act cytoprotectively during MI in the acute setting while this effect was less pronounced in the atherosclerosis model.

Connecting the Dots in the Neuroglobin-Protein Interaction Network of an Unstressed and Ferroptotic Cell Death Neuroblastoma Model

“…In support of this idea, a knockout of Ngb has been already detected to induce expression alterations of proteins linked to the glycolytic pathway [43], and recent research starts to ascribe immune-linked functions to Ngb as well. Ngb has been detected to be linked to astroglial antioxidant mechanisms [44], a neuroprotective interaction between mesenchymal stem cells and astrocytes [45] and the expression of inflammatory markers in the tissue surrounding an injury site [46]. In this study, we detected the interaction of hNgb with DHX9 to be reduced under erastin stress.…”

Lessons from the post-genomic era: Globin diversity beyond oxygen binding and transport

“…Of note, Ngb was shown to directly promote 14-3-3γ expression in a yet unknown way [ 226 , 227 ]. In line with these studies, overexpression of Ngb in several pathogenic cardiac models, including ischemia and isoproterenol-induced cardiac hypertrophy, resulted in reduced apoptosis, inflammation, hypertrophy, infarct size and promoted cardiomyocyte survival by acting on reactive oxygen and nitrogen species levels and thereby reducing oxidative stress [ 228 , 229 ]. Intriguingly, Tae and coworkers recently reported that rats exposed to side stream cigarette smoke displayed increased levels of Ngb, and to a lesser extent Cygb, in cerebral cortex and hippocampus, and suggested a role in the oxidative stress response [ 230 ].…”

Neuroglobin Expression Models as a Tool to Study Its Function

“…Subsequently, The Jackson Laboratory backcrossed these mice to a C57BL/6J background for at least five generations to generate the congenic commercially available strain: B6.Cg-Tg(CAG-Ngb,-EGFP)1Dgrn/J (007575, The Jackson Laboratory) or mNgb-Tg-1∗ ([62], Figure 3). By analogy with the original mNgb-Tg-1 mouse model, the derived congenic strain was used in different ischemic and hypoxic setups [62–64]. Although Ngb's cytoprotective function was confirmed during acute myocardial infarction, this effect was less pronounced in a mNgb-Tg-1∗ atherosclerosis model, where Ngb overexpression did not affect survival nor occurrence of myocardial infarcts ([64], Figure 4).…”

“…By analogy with the original mNgb-Tg-1 mouse model, the derived congenic strain was used in different ischemic and hypoxic setups [62–64]. Although Ngb's cytoprotective function was confirmed during acute myocardial infarction, this effect was less pronounced in a mNgb-Tg-1∗ atherosclerosis model, where Ngb overexpression did not affect survival nor occurrence of myocardial infarcts ([64], Figure 4). Intriguingly, for cerebral ischemia, a significant reduction in brain infarct volume was observed 24 hours after ischemia in mNgb-Tg-1∗ mice, but the infarct volume was found to be specific to the genetic background of the mice [62].…”