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  • The MOB and AOB are important in ungulates Keller and

    2024-05-25

    The MOB and AOB are important in ungulates (Keller and Levy, 2012, Sanchez-Andrade and Kendrick, 2009), which rely heavily on odorant information for social interactions (Baum and Cherry, 2015, Keller and Levy, 2012, Osada et al., 2014, Villagran and Ungerfeld, 2013). The release of GABA and glutamate in the MOB of ewes increases after parturition, and these increases are connected to the selective bond with their lambs (Keller and Levy, 2012). Furthermore, GABA and glutamate significantly increased in response to odorant memory (Sanchez-Andrade and Kendrick, 2009). Collectively, these findings suggest that arginases, which catalyze l-arginine, play an important role in both excitatory and inhibitory neurotransmission in the roe deer MOB and AOB.
    Acknowlegment This research was supported by the National Research Foundation of Korea (Grant number: NRF-2017R1A2B4012487).
    Introduction Cardiovascular diseases including acute myocardial infarction (AMI) are the leading cause of death worldwide (Pagidipati and Gaziano, 2013). Current treatment for AMI caused by a coronary artery occlusion is the restoration of blood flow (i.e., reperfusion) by means of a percutaneous intervention. Early revascularization rescues the myocardium at risk and reduces infarct size, which improves AMI-associated morbidity and mortality. However, reperfusion itself can damage myocardium, a phenomenon referred to as ischemia-reperfusion (I/R) injury. Several mechanisms have been linked to this phenomenon, including oxidative stress, calcium overload, inflammation and endothelial dysfunction (Hadi et al., 2005). Endothelial dysfunction is characterized by the reduced bioavailability of nitric oxide (NO) and has been identified as a therapeutic target. Myocardial NO bioavailability can be compromised by several factors, including decreased Thiazovivin and/or altered activity of endothelial NO synthase (eNOS), augmented production of reactive oxygen species (ROS) (e.g., anion superoxide [O2-]), and/or insufficient substrate availability (i.e., L-arginine) (Hadi et al., 2005). One of the mechanisms that reduces NO availability in the setting of I/R injury, is an increase arginase (Ar) activity. Arginase is an enzyme that competes with NOS for the common substrate, L-arginine. Under normal conditions, NOS metabolizes L-arginine into L-citrulline, producing NO in the process. Ar metabolizes L-arginine into L-ornithine and urea (Yang and Ming, 2014). Of note, an increased activity of Ar has been reported in several conditions associated with endothelial dysfunction, including diabetes mellitus and atherosclerosis, and is thought to contribute to disease pathophysiology (Romero et al., 2008; Berkowitz et al., 2003; Ryoo et al., 2006, Ryoo et al., 2008; Kan et al., 2015). Two different isoforms of Ar (1 and 2) have been described that differ mainly in their intracellular localization. Ar 1 is an enzyme expressed primarily in liver, endothelium, smooth muscle cells and cardiomyocytes. Ar 2 is localized in mitochondria of multiple tissues, including heart and vasculature (Yang and Ming, 2014). Compounds that increase NO availability by decreasing its metabolism or increasing its blood levels (e.g., NO donors, Ar inhibitors) to physiological levels have been shown to confer protection against I/R injury. In this regard, flavonoids, particularly (-)-Epicatechin (EPI), the most abundant flavanol in cacao, has been reported to inhibit Ar activity in cultured endothelial cells, thus increasing NO production (Schnorr et al., 2008). Recently, we demonstrated that EPI is able to reduce myocardial damage that was induced by permanent coronary occlusion or I/R in rats (measured 48h and 3 weeks after I/R) (Yamazaki et al., 2008) by ~ 50%. We also reported that EPI induced NO synthesis through the activation of eNOS in endothelial cells (Ramirez-Sanchez et al., 2010). The aim of the present study was to determine if EPI is able to interact and modulate myocardial Ar as well as to modify its levels and those of NOS. For this purpose, in silico modeling, in vitro activity assays and a rat model of I/R injury were used.