Abstract 19012: Genetic Deletion of 12/15 Lipoxygenase Delays Vascular Remodeling, Limits Cardiorenal Dysfunction and Improves Survival After Pressure Overload
Introduction: The lipid metabolizing enzyme 12/15lipoxygenase (12/15LOX) induces pro-inflammatory responses that may increase cardiovascular and renal complications.
Hypothesis: Deletion of 12/15LOX limits left ventricular (LV) hypertrophy associated perivascular inflammation and cardiorenal remodeling after pressure overload.
Methods and Results: 8-12 week old male C57BL/6J wild-type (WT; n=23) and 12/15LOX–/– mice (n=21) were subject to transverse aortic constriction (TAC) and monitored for 7, 28 and 56 days (d) post-TAC. Compared to WT, 12/15LOX-/-mice exhibited less LV dysfunction (echocardiography) and improved survival rates post-TAC. 12/15LOX-/- mice post-TAC also exhibited less LV hypertrophy and decreased lung edema. 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 when 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 α-SMA in WT-TAC mice at d28 and 56. In contrast, 12/15LOX-/- mice displayed continuity in the endothelium lining with reduced levels of α-SMA, suggesting improved vascular remodeling. Compared to WT, 12/15LOX-/- mice exhibited a diminished expression of NGAL in kidney, suggesting that 12/15LOX deletion reduced cardiorenal dysfunction after TAC. In WT-TAC mice, structural analyses of the kidney revealed glomerular swelling during the progression of heart failure together with decreases in the capsula glomeruli space and glomerular sclerosis compared to 12/15LOX–/– mice. Overall, markers of vascular and kidney dysfunctional were higher in WT TAC mice than 12/15LOX–/– TAC mice.
Conclusion: Deletion of 12/15LOX in mice leads to improved vascular and cardiorenal function during the progression of cardiac hypertrophy induced by pressure overload.
Author Disclosures: K. Ingle: None. V. Kain: None. D.G. Rokosh: None. S.D. Prabhu: None. G.V. Halade: Research Grant; Modest; NIH NCCAM- R00AT006704.
- © 2016 by American Heart Association, Inc.