Endothelial nitric oxide synthase inhibition triggers inflammatory responses in the brain of male rats exposed to ischemia‐reperfusion injury

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Pharmacological and genetic approaches have significantly advanced our knowledge of the role of nitric oxide (NO) and the different NO synthase (NOS) isoforms in cerebral ischemia. The neuronal (nNOS) and inducible (iNOS) isoforms are implicated in ischemia‐induced neurodegeneration, while endothelial NOS (eNOS) has a crucial role in maintaining cerebral blood flow and preventing neuronal injury (Samdani, Dawson, & Dawson, 1997; Srivastava, Bath, & Bayraktutan, 2012; Toda, Ayajiki, & Okamura, 2009). In fact, endothelial‐derived NO plays an important role in postischemic revascularization, including endothelial cell proliferation and migration, smooth muscle cell differentiation, angiogenic processes, and arterial‐venous differentiation (Cui et al., 2009; Gertz et al., 2006; Luque Contreras, Vargas Robles, Romo, Rios, & Escalante, 2006; Rudic et al., 1998). Accordingly, endothelial dysfunction, associated with reduced eNOS activity, contributes to the progression of the ischemic lesion through the impairment of cerebral microcirculation (Cui et al., 2009; Garry, Ezra, Rowland, Westbrook, & Pattinson, 2015). Pharmacological inhibition of eNOS by l‐N‐(1‐iminoethyl)ornithine (L‐NIO) has been shown to increase the expression of inflammatory mediators in the ischemic brain of rodents (Greco et al., 2017). Although eNOS has been suggested to contribute to inflammatory responses via the modulation of nuclear factor‐kappaB (NF‐kB) activity (Connelly et al., 2003; Connelly, Madhani, & Hobbs, 2005; Greco et al., 2011), the relevance of its immunomodulatory effects in ischemic stroke outcome has not been fully explored.
Small, noncoding microRNAs (miRNAs) have been implicated in posttranscriptional gene silencing in both pathogenic and pathological aspects of ischemic stroke (Rink & Khanna, 2011). In particular, the expression profile of the multifunctional miRNA miR‐155 is significantly affected by cerebral ischemia both in rodents and in humans (Choi et al., 2016; Lim et al., 2010; Liu et al., 2010). Pharmacological inhibition or gene deletion of miR‐155 promotes functional recovery in ischemic stroke models by improving microvascular integrity and by reducing the expression of inflammatory mediators (Caballero‐Garrido et al., 2015; Pena‐Philippides, Caballero‐Garrido, Lordkipanidze, & Roitbak, 2016; Wen et al., 2015). Interestingly, NO regulation of gene expression, particularly in immune processes and inflammation, has been associated with alterations of miR‐155 expression (Yuhas, Berent, & Ashkenazi, 2014). In turn, NF‐kB is critically involved in the upregulation of miR‐155 due to inflammatory stimuli (Gatto et al., 2008; Lee et al., 2014; Thompson, Vardinogiannis, & Gilmore, 2013), leading to the hypothesis that miR‐155 may contribute to the detrimental proinflammatory effects associated with eNOS inhibition during ischemia.
Thus, in this study, we aimed to investigate the effects of pharmacological inhibition of eNOS on the inflammatory response triggered by transient middle cerebral artery occlusion (tMCAo) in rats, by measuring gene expression of miR‐155‐5p, iNOS, and interleukin (IL)‐10 and by assessing the expression of proinflammatory immune phenotypes in the ischemic cortex.
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