Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment

Abstract

Interstitial fibrosis plays a key role in the development and progression of heart failure. Here, we show that an enzyme that crosslinks collagen—Lysyl oxidase-like 2 (Loxl2)—is essential for interstitial fibrosis and mechanical dysfunction of pathologically stressed hearts. In mice, cardiac stress activates fibroblasts to express and secrete Loxl2 into the interstitium, triggering fibrosis, systolic and diastolic dysfunction of stressed hearts. Antibody-mediated inhibition or genetic disruption of Loxl2 greatly reduces stress-induced cardiac fibrosis and chamber dilatation, improving systolic and diastolic functions. Loxl2 stimulates cardiac fibroblasts through PI3K/AKT to produce TGF-β2, promoting fibroblast-to-myofibroblast transformation; Loxl2 also acts downstream of TGF-β2 to stimulate myofibroblast migration. In diseased human hearts, LOXL2 is upregulated in cardiac interstitium; its levels correlate with collagen crosslinking and cardiac dysfunction. LOXL2 is also elevated in the serum of heart failure (HF) patients, correlating with other HF biomarkers, suggesting a conserved LOXL2-mediated mechanism of human HF.

Cardiomyocyte calcineurin is required for the onset and progression of cardiac hypertrophy and fibrosis in adult mice

“…8E). As reported for transaortic constriction-induced CH [34], AngII also upregulated the other Lox family members (Loxl1, Loxl2, Loxl3, and Loxl4) in the heart (Fig. 9).…”

“…In recent years, new factors have been identified and characterized that trigger and maintain the myocardial fibrotic response in different cardiac diseases . An important role in pathological cardiac fibrosis was recently described for the lysyl oxidase (Lox) family of enzymes, which catalyze collagen assembly . Here, we show that suppression of cardiac Cn impairs the transcriptional expression of Lox , which is involved in the progression of a pathological fibrotic response in the heart.…”

Lysyl Oxidase Like‐2 (LOXL2): An Emerging Oncology Target

“…AB0023 has been tested in cell lines and mice models before the humanized version entered clinical testing. AB0023 has been studied in the context of LOXL2 involvement in interstitial fibrosis and heart failure in mice dosed at 30 mg kg −1 twice a week . The transaortic constriction dysfunction was less seen in the treated mice and the transaortic constriction stressed heart also stabilized left ventricular fractional shortening .…”

“…AB0023 has been studied in the context of LOXL2 involvement in interstitial fibrosis and heart failure in mice dosed at 30 mg kg −1 twice a week . The transaortic constriction dysfunction was less seen in the treated mice and the transaortic constriction stressed heart also stabilized left ventricular fractional shortening . It was concluded that LOXL2 has an effect on interstitial fibrosis and the dysfunction of the heart as they are involved in the activation of myofibroblasts, promoting the production of collagen within cardiac tissue …”

Selective LOXL2 inhibition: potent antifibrotic effects in ongoing fibrosis and fibrosis regression

“…Likewise, targeting LOXL2 delivered promising results in other diseases such as reduction in stress-induced cardiac fibrosis 9. However, less enthusiastic results were obtained in idiopathic pulmonary fibrosis using a monoclonal antibody 10…”