Genetic deletion of 12/15 lipoxygenase delays vascular remodeling and limits cardiorenal dysfunction after pressure overload

• Published in: Journal of Molecular and Cellular Cardiology Plus (Online) Vol. 5; p. 100046
• Main Authors: Lee, Dae Hyun, Kain, Vasundhara, Wang, Da-Zhi, Rokosh, Donald G., Prabhu, Sumanth D., Halade, Ganesh V.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.09.2023; Elsevier
• Subjects: Heart failure; Inflammation-resolution signaling; Lipid mediators; Lipoxygenase; Pressure overload; Transverse aortic constriction; Heart failure; Pressure overload; Transverse aortic constriction; Inflammation-resolution signaling; Lipid mediators; Lipoxygenase
• ISSN: 2772-9761; 2772-9761
• DOI: 10.1016/j.jmccpl.2023.100046

The lipid metabolizing enzyme 12/15 lipoxygenase (12/15LOX) induces proinflammatory responses that may increase cardiovascular and renal complications after cardiac insult. To define the role of 12/15LOX, 8–12-week-old male C57BL/6J wild-type (WT; n = 49) and 12/15LOX−/− mice (n = 50) were subject to transverse aortic constriction (TAC) and monitored for 7, 28, and 56 days (d) post-TAC. Compared with WT, 12/15LOX−/− mice experienced less left ventricle (LV) dysfunction with limited LV hypertrophy and lung edema post-TAC. 12/15LOX deletion decreased TAC-induced proinflammatory mediators 12-HETE and prostaglandins with modulation in mir-7a-5p, mir 26a-5p, miR-21e-5p, and miR-107-3p during chronic remodeling period (after d28). At d7 post-TAC, 12/15LOX−/− mice showed increased cardiac gene expression of Arg-1 and the prostanoid receptors EP2 and EP4. The EP4 receptor expression was consistently elevated from d7 till d56 in 12/15LOX−/− mice post-TAC compared with WT controls. Post-TAC, wheat germ agglutinin staining revealed less cardiomyocyte hypertrophy at d28 and d56 in 12/15LOX−/− mice compared with WT. TAC-induced vascular remodeling was marked by disruption in the endothelium, evident by irregular CD31 staining and increased alpha-smooth muscle actin (α-SMA) in WT mice at d28 and d56. Compared to WT, 12/15LOX−/− mice exhibited a diminished expression of NGAL in the kidney, suggesting that 12/15LOX−/− reduced cardiorenal dysfunction post-TAC. In WT-TAC mice, structural analyses of the kidney revealed glomerular swelling during the maladaptive phase of heart failure, with decreases in the capsula glomeruli space and glomerular sclerosis compared to 12/15LOX−/− mice. Overall, vascular and kidney inflammation markers were higher in WT than in 12/15LOX−/− post-TAC. Thus, deletion of 12/15LOX limits LV hypertrophy associated with perivascular inflammation and cardiorenal remodeling after pressure overload. Deficiency of 12/15 LOX serves a dual role in delaying an early adaptive interstitial remodeling with long-term protective effects on cardiac hypertrophy and cardiac fibrosis and detrimental adverse vascular remodeling during later maladaptive remodeling after pressure overload. [Display omitted] •Deletion of 12/15LOX improved ventricular function and reduced ventricular hypertrophy following pressure overload in chronic heart failure.•Lack of 12/15LOX reduces pro-inflammatory 12-HETE and upregulates pro-resolution mediators thereby limited ventricular remodeling.•12/15LOX deletion reduces fibrotic and ventricular remodeling, however amplifies vascular remodeling following pressure overload.