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Endocannabinoids act as a stress response system; simultaneously, the modulation of this system has emerged a novel approach for the therapy of cardiovascular disorders. We investigated the protective effects of the chronic administration of the fatty acid amide hydrolase inhibitor URB597 on morphology, pro-inflammatory and anti- inflammatory cytokine, the cytoplasm-nuclear distribution of JAK2/STAT3, and NF-kB and Nrf2/HO-1 signaling in the left ventricle of female and male rats exposed to chronic unpredictable stress. Our results show that URB597 treatment exhibits an antidepressant-like effect, decreases the heart/body weight ratio, prevents the hypertrophy of cardiomyocytes, and reduces the increased level of IL-6 in the wall of the left ventricle of stressed female and male rats. The phosphorylation levels of JAK2 and STAT3 in the ventricle of male rats treated with URB597 were declined, whereas in female rats the decrease of STAT3 was observed. In addition, URB597 reduced increased NF-kB in both females and males and increased the expression of Nrf2 and HO-1 protein in the cytosol of male rats, whereas did not affect their levels in females. Cardioprotective effects of URB597 could be linked to the ability to inhibit the JAK2 in males and the STAT3 inflammatory signaling pathways in both females and males. Key words: endocannabinoids, cardiac hypertrophy, cytokines, JAK2/STAT3, male and female rats, 1. Introduction Stress includes etiological mechanisms for depression and heart injury (Redfors et al. 2013). The physiological response to stress is initiated by the activation of the sympatho-adrenomedullary system and [...]

Endocannabinoids act as a stress response system; simultaneously, the modulation of this system has emerged a novel approach for the therapy of cardiovascular disorders. We investigated the protective effects of the chronic administration of the fatty acid amide hydrolase inhibitor URB597 on morphology, pro-inflammatory and anti-inflammatory cytokine, the cytoplasm-nuclear distribution of JAK2/STAT3, and NF-κB and Nrf2/HO-1 signaling in the left ventricle of female and male rats exposed to chronic unpredictable stress. Our results show that URB597 treatment exhibits an antidepressant-like effect, decreases the heart/body weight ratio, prevents the hypertrophy of cardiomyocytes, and reduces the increased level of IL-6 in the wall of the left ventricle of stressed female and male rats. The phosphorylation levels of JAK2 and STAT3 in the ventricle of male rats treated with URB597 were declined, whereas in female rats the decrease of STAT3 was observed. In addition, URB597 reduced increased NF-κB in both females and males and increased the expression of Nrf2 and HO-1 protein in the cytosol of male rats, whereas did not affect their levels in females. Cardioprotective effects of URB597 could be linked to the ability to inhibit the JAK2 in males and the STAT3 inflammatory signaling pathways in both females and males. [ABSTRACT FROM AUTHOR]

Introduction: The present study examined the effects of fatty acid amide hydrolase inhibitor URB597 on the level of plasma catecholamine and their content, synthesis, and degradation in the adrenal medulla of male and female rats subjected to chronic unpredictable stress (CUS). Material and Methods: Male and female Wistar rats were exposed to the 6 weeks of CUS and treated intraperitoneally with either 0.3 mg/kg/day of URB597 or vehicle in the last 2 weeks of stress protocol. Catecholamines' plasma levels and catecholamines' levels in adrenal medulla were examined using Elabscience ELISA kits. Western blot analysis was used to detect the protein in the medulla. Results: The results of our experiment showed that adrenal weights and catecholamine of unstressed control were higher in females and that CUS induced further enlargement of adrenal glands and catecholamine content and its synthesis compared to male rats. CUS caused an increase of plasma norepinephrine and depletion of norepinephrine content as well as unchanged synthesis and degradation of catecholamine in the adrenal medulla of male rats. URB597 reduced enlarged adrenals and catecholamine content and its synthesis in stressed female rats. URB597 reduces increased plasma norepinephrine and restores its content in the adrenal medulla, unchanging the expression of enzyme synthesis, while reduced protein levels of monoamine oxidase A in male rats are exposed to CUS. Discussion: Our results support the role of endocannabinoids as an antistress mechanism that inhibits elevated adrenomedullary activation and promotes its recovery to baseline in both male and female stressed rats. [ABSTRACT FROM AUTHOR]