Abstract 11713: LOX-1 Knockout Mice Preserve Against Doxorubicin-Induced Cardiomyopathy
Purpose: Lectin-like oxidized LDL receptor-1 (LOX-1) regulates cardiac remodeling after ischemia-reperfusion and Angiotensin II infusion. These suggest that the oxidative stress-LOX-1 pathway is important in the pathology of heart failure. Oxidative stress is one of the major factors in doxorubicin (Dox)-induced cardiomyopathy. Therefore, we presumed that LOX-1 contributes to the pathogenesis of Dox-induced cardiomyopathy.
Methods: Cardiomyopathy was induced by a single injection of Dox (20 mg/kg IP) into wild-type (WT) mice and LOX-1 knockout (KO) mice. We performed echocardiography 0,7,14 and 28 days after Dox injection. IL-1β and TNF-α were measured by ELISA. NF-κB, caspase-3 and sarcomeric protein expressions were assessed by Western blotting. Quantitative assessments, including fibrotic area (% of total tissue area) and cell size, were carried out using a multipurpose image processor.
Results: 28 days after Dox injection, both LVEDD and LVESD of LOX-1 KO mice were smaller than those of WT mice (p<0.01), while fractional shortening was significantly higher in KO mice compared with WT mice (P<0.01). Production of IL-1β and TNF-α after Dox administration was suppressed in KO mice compared with WT mice (p<0.01). Western blotting showed that NF-κB and caspase-3 activation were less in LOX-1 KO mice than in WT mice 24 hours. Western blotting also showed that LOX-1 deletion rescued expressions of sarcomeric proteins (MHC and troponin-I) reduced by DOX. The numbers of TUNEL-positive nuclei after Dox were much less in LOX-1 KO mice than in WT mice (p<0.01). The transverse diameters of cardiomyocytes from WT mice receiving DOX were smaller than in LOX-1 KO mice receiving DOX (p<0.01). Similarly we found more fibrosis in WT mice than in LOX-1 KO mice receiving DOX (P<0.01).
Conclusions: Our results suggest that LOX-1 plays important roles in the pathology of cardiomyopathy induced by DOX administration. The deletion of LOX-1 suppressed NF-κB activation and production of cytokines, which may lead to improvements in cardiac function and suppression of remodeling, including cell death, fibrosis and degenerative changes in the cardiomyocytes.
- © 2011 by American Heart Association, Inc.