Gidday, J. M. | Search bioRxiv

bioRxiv2020

Intermittent hypoxia promotes functional neuroprotection from retinal ischemia in untreated first-generation offspring

Environmental stimuli can promote short- or long-lasting changes in phenotype through epigenetics. Under certain circumstances, induced phenotypes can be passed through the germline to subsequent generations, providing a novel mechanistic basis for disease heritability. In the present study, we tested the hypothesis that repetitively exposing parents to a nonharmful epigenetic stimulus can promote disease resilience in offspring. Male and female mice were mated following brief exposures to mild systemic hypoxia every other day for 16 weeks. Electroretinographic determinations of postischemic function in response to transient unilateral retinal ischemia in their 5-month-old F1 progeny revealed significant resilience to injury relative to animals derived from normoxic control parents. Mass spectrometry identified hundreds of differentially expressed proteins between protected and injured retinae; bioinformatic analyses of the pathways and networks these proteins comprise provided specific mechanistic insights into the molecular manifestation of this injury-resilient phenotype. Thus, epigenetics can modify heritability to promote disease resilience.

neuroscience↗

bioRxiv2019

Sexual Differences in Mitochondrial Proteins in Rat Cerebral Microvessels: A Proteomic Approach

Sex differences in mitochondrial numbers and function are present in large cerebral arteries, but it is unclear whether these differences extend to the microcirculation. We performed an assessment of mitochondria-related proteins in cerebral microvessels (MVs) isolated from young, male and female, Sprague-Dawley rats. MVs composed of arterioles, capillaries, and venules were isolated from the cerebrum and used to perform a 3 vs. 3 quantitative, multiplexed proteomics experiment utilizing tandem mass tags (TMT), coupled with liquid chromatography/mass spectrometry (LC/MS). MS data and bioinformatic analyses were performed using Proteome Discoverer version 2.2 and Ingenuity Pathway Analysis. We identified a total of 1,969 proteins, of which 1,871 were quantified by TMT labels. Sixty-four proteins were expressed significantly (p < 0.05) higher in female samples compared with male samples. Females expressed more mitochondrial proteins involved in energy production, mitochondrial membrane structure, anti-oxidant enzyme proteins, and those involved in fatty acid oxidation. Conversely, males had higher expression levels of mitochondria-destructive proteins. We validated our key Proteomics results with western blotting. Our findings reveal, for the first time, the full extent of sexual dimorphism in the mitochondrial metabolic protein profiles of MVs, which may contribute to sex-dependent cerebrovascular and neurological pathologies. SynopsisEnergy-producing proteins in the cerebral microvessels (MVs) of male and female rats were examined by quantitative discovery-based proteomics to gain insight into the sex-dependent etiology of cardiovascular and neurological diseases. Females expressed more mitochondrial proteins involved in energy production, membrane structure, anti-oxidant activity, and fatty acid oxidation. In contrast, males exhibited more mitochondria-destructive proteins such as mitochondrial eating protein. Our findings reveal for the first time the sexual dimorphism of mitochondria-related proteins in cerebral MVs, which may explain functional sex-related differences in MVs during health and in the etiology of neurological pathologies of cerebrovascular origin.

neuroscience↗