Deletion of LOX-1 Protects against Heart Failure Induced by Doxorubicin

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.

Knockdown of lectin-like oxidized low-density lipoprotein-1 ameliorates alcoholic cardiomyopathy via inactivating the p38 mitogen-activated protein kinase pathway

“…This was consistent with Li et al’s findings [ 27 ]. Furthermore, abrogation of LOX-1 also exerted protective roles against doxorubicin-induced myocardial inflammation, fibrosis and degeneration [ 28 ]. Therefore, LOX-1 owned fibrotic roles in cardiovascular disease.…”

Sulforaphane protection against the development of doxorubicin‐induced chronic heart failure is associated with Nrf2 Upregulation

“…DOX a typical anthracycline chemotherapeutic, is extremely effective against many tumors and is widely used. However, it is known to have adverse effects on various tissues via oxidative stress . Cardiac damage by DOX manifests as histopathological changes that lead to myofibrillar disarray and loss, and dilated cardiomyopathy .…”

Inflammation – Cause or Consequence of Heart Failure or Both?

“…TNF-α also induces TGF-ß [ 68 ] and increases the expression of cardiac fibroblast lysyl oxidase (LOX) expression through TGF-β and PI3Kinase signaling pathways [ 69 ]. LOX belongs to a family of enzymes [ 70 ], including LOX-like 2, responsible for the crosslinking of ECM proteins, including collagen types I and III. The relevance of LOX-like 2 as therapeutic target of cardiac fibrosis and as biomarker for HF has recently been demonstrated [ 71 ].…”