Abstract
UCP2 maps nearby the lod score peak of STR1-stroke QTL in the SHRSP rat strain. We explored the potential contribution of UCP2 to the high-salt diet (JD)-dependent increased stroke susceptibility of SHRSP. Male SHRSP, SHRSR, two reciprocal SHRSR/SHRSP-STR1/QTL stroke congenic lines received JD for 4 weeks to detect brain UCP2 gene/protein modulation as compared with regular diet (RD). Brains were also analyzed for NF-κB protein expression, oxidative stress level and UCP2-targeted microRNAs expression level. Next, based on knowledge that fenofibrate and Brassica Oleracea (BO) stimulate UCP2 expression through PPARα activation, we monitored stroke occurrence in SHRSP receiving JD plus fenofibrate versus vehicle, JD plus BO juice versus BO juice plus PPARα inhibitor. Brain UCP2 expression was markedly reduced by JD in SHRSP and in the (SHRsr.SHRsp-(D1Rat134-Mt1pa)) congenic line, whereas NF-κB expression and oxidative stress level increased. The opposite phenomenon was observed in the SHRSR and in the (SHRsp.SHRsr-(D1Rat134-Mt1pa)) reciprocal congenic line. Interestingly, the UCP2-targeted rno-microRNA-503 was significantly upregulated in SHRSP and decreased in SHRSR upon JD, with consistent changes in the two reciprocal congenic lines. Both fenofibrate and BO significantly decreased brain microRNA-503 level, upregulated UCP2 expression and protected SHRSP from stroke occurrence. In vitro overexpression of microRNA-503 in endothelial cells suppressed UCP2 expression and led to a significant increase of cell mortality with decreased cell viability. Brain UCP2 downregulation is a determinant of increased stroke predisposition in high-salt-fed SHRSP. In this context, UCP2 can be modulated by both pharmacological and nutraceutical agents. The microRNA-503 significantly contributes to mediate brain UCP2 downregulation in JD-fed SHRSP.
Highlights
The SHRSP represents a suitable animal model for the investigation of the etiopathogenetic basis of hypertensive target organ damage.[1]
Both inflammatory and oxidative stress markers were decreased in the SHRSP-derived stroke congenic line, carrying the SHRSR/ STR1 chromosomal fragment, whereas these markers increased significantly in the SHRSR-derived stroke congenic line carrying the SHRSP/STR1 chromosomal fragment
These results confirmed that, whenever UCP2 expression was downregulated, such as in JD-fed SHRSP and JD-fed (SHRsr.SHRsp-(D1Rat134-Mt1pa)), the degree of inflammation and of oxidative stress increased. No increase of these processes was detected in the brains of both JD-fed SHRSR and JD-fed (SHRsp.SHRsr(D1Rat134-Mt1pa)), both carrying higher levels of brain UCP2 expression
Summary
The SHRSP represents a suitable animal model for the investigation of the etiopathogenetic basis of hypertensive target organ damage.[1]. ROS production in endothelial cells and preserved endothelial function by reducing ROS levels.[13,14] Consistently with its ability to decrease endogenous mitochondrial ROS production and to maintain normal mitochondrial membrane potential and ATP levels, a neuroprotective effect of UCP2 has been previously described both in vitro and in vivo.[15,16,17,18,19,20,21] We previously reported an age-related spontaneous decrease of UCP2 gene and protein expression only in the brain of SHRSP, preceding spontaneous stroke occurrence at 1 year of age.[22]. We have shown that, in association with increased renal injury, JD significantly downregulates UCP2 gene and protein expression in the kidneys of SHRSP, but not of SHRSR.[23] Consistent findings were obtained in the kidneys of SHRSR/SHRSP-derived stroke congenic lines, depending. Exposure of primary renal proximal tubular epithelial cells isolated from SHRSP to high-NaCl medium led to UCP2 downregulation and reduced viability, which was rescued by recombinant
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