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

Dae Hyun Lee, Vasundhara Kain, Da Zhi Wang, Donald G. Rokosh, Sumanth D. Prabhu, Ganesh V. Halade

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number100046
JournalJournal of Molecular and Cellular Cardiology Plus
Volume5
DOIs
StatePublished - Sep 2023

Keywords

  • Heart failure
  • Inflammation-resolution signaling
  • Lipid mediators
  • Lipoxygenase
  • Pressure overload
  • Transverse aortic constriction

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