Abstract
Oxidative stress is one of the major factors in doxorubicin (DOX)-induced cardiomyopathy. Lectin-like oxidized low-density lipoprotein (oxLDL) receptor-1 (LOX-1) plays an important role to regulate cardiac remodeling and oxidative stress after ischemia-reperfusion. Therefore, we examined whether or not LOX-1 contributes to the pathogenesis of DOX-induced cardiomyopathy. Cardiomyopathy was induced by a single intraperitoneal injection of DOX into wild-type (WT) mice and LOX-1 knockout (KO) mice. Echocardiography and catheter-based hemodynamic assessment apparently revealed preserved left ventricular (LV) fractional shortening (FS) and cavity size of LOX-1 KO mice compared with those of WT mice after DOX administration. Less production of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1ß) was observed in LOX-1 KO mice than WT mice after DOX administration. Western blotting analysis also showed lower activation of nuclear factor κB (NF-κB) and p38 mitogen-activated protein kinase (MAPK) in LOX-1 KO mice treated with DOX than WT mice treated with DOX. In fact, NF-κB-dependent gene expressions of LOX-1 and vascular cell adhesion molecule-1 (VCAM-1) were suppressed in LOX-1 KO mice treated with DOX compared with WT mice treated with DOX. Therefore, histological analyses showed attenuation of leukocyte infiltration and cardiac fibrosis in LOX-1 KO mice compared with WT mice. Meanwhile, extracellular signal-regulated kinase MAPK (ERK) inactivation and decreased expression of sarcomeric proteins and related transcription factor GATA-4 in WT mice treated with DOX administration were not seen in LOX-1 KO mice treated with DOX administration and WT and LOX-1 KO mice treated with vehicle. Decreased expression of sarcometric proteins resulted in smaller diameters of cardiomyocytes in WT mice than in LOX-1 KO mice after DOX treatment. The expression of LOX-1 in cardiomyocytes was much more abundant than that in endothelial cells, fibroblasts and inflammatory cells. Endothelial cells, fibroblasts and inflammatory cells treated with DOX showed no elevated LOX-1 expression compared with those treated with vehicle. However, cardiomyocytes treated with DOX showed much more expression of LOX-1 than those treated with vehicle. Immunohistochemistry study also showed that LOX-1 expression was strongly elevated in cardiomyocytes in the heart tissue of mice treated with DOX in vivo. We conclude that LOX-1 in cardiomyocytes plays the most important roles in the pathology of DOX-induced cardiomyopathy. LOX-1 deletion altered the LOX-1-related signaling pathway, which led to improvements in cardiac function, myocardial inflammation, fibrosis and degenerative changes after DOX treatment.
Highlights
The lectin-like oxidized low-density-lipoprotein receptor (LOX-1), which belongs to the type D scavenger receptors, was initially cloned from aortic endothelial cells in 1997 [1,2,3]
M-mode echocardiography demonstrated that left ventricular (LV) chamber diameters of WT mice were significantly dilated compared with those of lipoprotein (oxLDL) receptor-1 (LOX-1) KO mice at 28 days after DOX administration, but there were no differences in LV chamber diameters between WT mice and LOX-1 KO mice treated with vehicle (Fig 1A)
WT mice treated with DOX presented larger LVDd and Ds, smaller fractional shortening (FS), SV and CO, and thinner IVSd and PWd relative to the other three groups of mice, but HR and LV mass of WT mice treated with DOX were not different from those of the other three groups of mice (Table 1)
Summary
The lectin-like oxidized low-density-lipoprotein receptor (LOX-1), which belongs to the type D scavenger receptors, was initially cloned from aortic endothelial cells in 1997 [1,2,3]. LOX-1 plays a role in oxLDL-induced apoptosis of vascular smooth muscle cells and in the production of matrix metalloproteinases, which can cause plaque rupture and lead to acute coronary syndrome [11,12,13,14,15,16]. The role of LOX-1 after remodeling following ischemia–reperfusion (I–R) was been investigated by other groups [12, 21]. They reported that significantly less necrosis in LOX-1 KO mice was found in WT mice after I-R in the hearts
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