Abstract Body: Background: Patients with hypertension (HTN) are almost 3 times more likely to have a stroke than non-hypertensive individuals. HTN is associated with oxidative stress (OS), exacerbated inflammation, and vascular remodeling. In experimental models, normotensive Sprague-Dawley (SD) and Spontaneously Hypertensive Rats (SHR) show different susceptibilities and outcomes to ischemic stroke. We propose that better understanding of the modulation in gene expression profile in HTN brains may provide critical insight into this complex process.
Methods: We focused on transcriptomic characterization of OS, inflammatory, and apoptosis pathway specific genes in SD and SHR brains before and after ischemic stroke. Middle Cerebral Artery Occlusion was used to induce focal ischemia/reperfusion injury (I/R). Using pathway specific arrays containing 84 selected genes, we performed a transcriptome analysis in the brain cortical regions. Fold-changes in gene expression were determined using the 2^−ΔΔCt method.
Results: In no-stroke SHR brain, HTN was associated with increased levels of pro-inflammatory genes including chemokine ligand (CCL)5 (3.0-fold), IL-6 (3.3-fold), and TNF superfamily member 7 (14-fold) as compared to normotensive SD rats without stroke. On the other hand, Mitogen-activated protein kinase 13, involved in tissue remodeling and cell proliferation was significantly decreased in SHR brains. However, following I/R, expression of redox signaling genes including aldehyde oxidase 1 (3.4 fold), dual oxidase 1 (2.5-fold), and lactoperoxidase (3.3-fold) were upregulated in SHR brains as compared to SD rat brains. This was linked to a dysregulation in inflammatory response genes including SELE (2.8-fold), IL-1β (2-fold), and CCL21 (3.2-fold). The downstream effects of OS and inflammation on apoptotic process was supported by an upregulated expression of pro-apoptotic genes, including caspases-3,6,12 (2.1,1.7, 3.4-fold), CIDEA (1.7-fold), FAS (1.7-fold), and PYCARD (2-fold). These data indicate that OS and inflammatory pathways are further over-activated in hypertensive rat brains.
Conclusion: Our data show that the expression of genes involved in OS and inflammation are coordinately upregulated as a function of HTN, which may worsen the outcome of ischemic stroke by likely regulating vascular remodeling, neuronal apoptosis, and blood brain barrier functions. Further studies focusing on these key genes may open up new ways to mitigate HTN-linked post-stroke brain damage.