Key result
LOXL2 inhibitor LOXL2-IN-1 reduces Angiotensin II-induced AF vulnerability, hypertrophy, and fibrosis in mice.
Why the study?
Ang II-induced atrial fibrosis promotes AF development, and LOXL2 is implicated in matrix remodeling and fibrogenesis, but its specific role and therapeutic potential in AF remain to be elucidated.
Does LOXL2 inhibition attenuate Angiotensin II-induced atrial fibrosis and vulnerability to atrial fibrillation in mice?
Does LOXL2 inhibition attenuate Angiotensin II-induced atrial fibrosis and vulnerability to atrial fibrillation in mice?
LOXL2 inhibition prevents Angiotensin II-induced atrial fibrosis and reduces vulnerability to atrial fibrillation in a mouse model, highlighting a potential novel therapeutic target for AF.
LOXL2 inhibition merits further AF study; leaves open translation from mouse models to patients.
OBJECTIVES: Angiotensin II (Ang II)-induced atrial fibrosis plays a vital role in the development of atrial fibrillation (AF). Lysyl oxidase-like 2 (LOXL2) plays an essential role in matrix remodeling and fibrogenesis, indicating it may involve fibrosis-associated diseases. This study aims to elucidate the role of LOXL2 in AF, and its specific inhibitor can suppress Ang II-induced inflammatory atrial fibrosis and attenuate the enhanced vulnerability to AF. METHODS: Male mice C57BL/6 were subcutaneously infused with either saline or Ang II (2 mg/kg/day) for 4 weeks. DMSO or LOXL2 inhibitor LOXL2-IN-1 hydrochloride (LOXL2-IN-1) at a dose of 100 μg/kg/day were intraperitoneally injected once daily for 4 weeks. Morphological, histological, and biochemical analyses were performed. AF was induced by transesophageal burst pacing in vivo. RESULTS: Expression of LOXL2 was increased in serum of AF patients and Ang II-treated mice. LOXL2-IN-1 significantly attenuated Ang II-induced AF vulnerability, cardiac hypertrophy, atrial inflammation, and fibrosis. LOXL2-IN-1 suppressed Ang II-induced expression of transforming growth factor beta-1 (TGF-β1) and collagen I and phosphorylation of Smad2/3 in atrial tissue. CONCLUSIONS: LOXL2 is a target of AF, and its inhibitor prevents atrial fibrosis and attenuated enhanced vulnerability to AF potentially through the TGF-β/Smad pathway.
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Wu et al. (2021) studied Atrial fibrillation and atrial fibrosis. LOXL2 inhibitor LOXL2-IN-1 hydrochloride vs. DMSO and Saline was evaluated on Ang II-induced AF vulnerability, cardiac hypertrophy, atrial inflammation, and fibrosis. LOXL2 inhibitor LOXL2-IN-1 significantly attenuated Angiotensin II-induced atrial fibrillation vulnerability, cardiac hypertrophy, atrial inflammation, and fibrosis in male mice.
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