Norfloxacin hydrochloride LOXs and CYPs are a series of

LOXs and CYPs are a series of iron-containing enzymes that metabolize arachidonic Norfloxacin hydrochloride to form biologically active products, such as epoxyeicosatrienoic acids (EETs) hydroperoxyeicosatetraenoic acids (HETEs), prostaglandins, leukotrienes and thromboxanes [6]. Among these mediators, 12/15LOX has gained particulate attention because of its increased expression in inflammatory diseases, such as atherosclerosis, diabetes and diabetic cardiomyopathy [[6], [7], [8]]. 12/15LOX forms unstable 12(S)-HETE, which can activate a signaling cascade leading to cytokine-induced cell damage [9,10]. Transgenic expression of 12/15LOX specifically in cardiomyocytes versus macrophage results in divergent effects on atheroprogressive inflammation and atherogenic cardiac pathology [11]. Disruption of LOXs, COX, and CYPs alters the metabolic transformation of arachidonic acid or other essential fatty acids to lipid mediators that have differential effects on resolving and non-resolving inflammatory responses [[12], [13], [14]].
Methods
Results
Discussion Heart failure secondary to MI is characterized by sustained inflammation and ventricular dilation. This pathological feature of cardiac remodeling is associated with decreased LV function and lower survival [2,3]. The current study focused on understanding the role of 12/15LOX in post-MI LV remodeling and survival. Here, we established that, 12/15LOX deletion in the post-MI setting leads to: 1) improved survival up to 28 d; 2) decreased levels of 12(S)-HETE, and increased levels of CYP2J-derived bioactive EETs; 3) altered leukocyte phenotype with increased N2 type neutrophils and M2 type Ly6Clow and CD206+ macrophages; 4) increased HO-1 expression in alternative macrophages that promotes post-MI healing; and 5) reduced collagen deposition with less myofibroblast differentiation. Thus, 12/15LOX deletion improved LV function by promoting effective resolution of inflammation, modulating leukocytes toward a reparative phenotype, and delaying ECM deposition post-MI (Fig. 7).
Conflict of interest
Acknowledgements This work was supported in part by the National Institutes of Health [AT006704], [HL132989] and Pittman Scholar Award to G.V.H., NIHR01 HL125735 and VA I01 BX002706 to S.D.P, and American Heart Association postdoctoral fellowship [POST31000008] to V. K. Funds for the mass spectrometer used in this study were provided by the UAB Health Services Foundation General Endowment Fund to S. B. Authors are thankful to Dr. Darryl C. Zeldin, NEIHS for proving CYP2J antibody and recombinant protein for the present study.
Introduction The transformation of arachidonic acid to 12S-hydroxy-5,8,10,14-eicosatetraenoic acid (12S-HETE) was first demonstrated in human and bovine platelets [1], [2], and this was the first documented evidence of a lipoxygenase in the animal kingdom. The platelet enzyme is now designated as 12S-lipoxygenase because it introduces molecular oxygen into arachidonic acid to form 12-hydroperoxyeicosatetraenoic acid (12S-HPETE) as the primary product. During the last 10 years a number of 12-lipoxygenases have been discovered including isoforms of 12S-lipoxygenases and a 12R-lipoxygenase that produces a 12-hydroperoxy derivative with R-configuration [3]. There are three 12S-lipoxygenase isoforms that are named after the cells where they were originally discovered; platelet, leukocyte and epidermis [3], [4], [5], [6], [7], [8]. Despite intensive research on the role of the 12S-lipoxygenases, our understanding of the biological significance of the enzymes and the major product 12S-HETE is still relatively limited. Several excellent reviews on the lipoxygenases have appeared in the last 5 years [3], [4], [5], [6], [7], [8]. This article will focus on recent research advances in studies of the 12S-lipoxygenase isoforms, and we will discuss the functional significance of the enzymes in certain biological systems as well as the possible clinical relevance of the enzymes.