LOXL2 Inhibitor Attenuates Angiotensin II-Induced Atrial Fibrosis and Vulnerability to Atrial Fibrillation through Inhibition of Transforming Growth Factor Beta-1 Smad2/3 Pathway

2021 ◽  
pp. 1-11
Author(s):  
Yingbiao Wu ◽  
Jin Can ◽  
Shuwen Hao ◽  
Xun Qiang ◽  
Zhongping Ning
Keyword(s):  
Atrial Fibrillation ◽  
Angiotensin Ii ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Specific Inhibitor ◽  
Matrix Remodeling ◽  
Ang Ii ◽  
Atrial Fibrosis ◽  
Growth Factor Beta

<b><i>Objectives:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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. <b><i>Conclusions:</i></b> 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.

Abstract 4278: Angiotensin II Receptor Antagonism and Transforming Growth Factor Beta and SMAD Signalling in Thoracic Aortic Aneurysm: Implications for Aneurysm Progression

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Maria Nataatmadja ◽  
Jennifer West ◽  
Malcolm West
Keyword(s):  
Angiotensin Ii ◽  
Growth Factor ◽  
Aortic Aneurysm ◽  
Transforming Growth Factor Beta ◽  
Thoracic Aortic Aneurysm ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Neointimal Hyperplasia ◽  
Growth Factor Beta ◽  
Smad3 Expression

Increased expression of transforming growth factor-beta (TGFβ) and Smad3 is associated with fibrosis and inflammatory cell infiltration in abdominal aortic aneurysm. In Smad3-null mice there is reduced extracellular matrix (ECM) deposition but enhanced neointimal hyperplasia in response to vascular injury suggesting a TGFβ/Smad3 role in ECM regulation and cell proliferation. In vitro studies show that exogenous TGFβ administration leads to phosphorylation and nuclear translocation of Smad3 while angiotensin II (AngII) induces fibrosis through TGFβ and Smad3 pathways. We investigated TGFβ/Smad3 signaling using immunohistochemical and cell culture studies in thoracic aortic aneurysm tissue derived from subjects with Marfan syndrome (MFS; 3M, 2F, 46±24yr, mean +/−SD) and bicuspid aortic valve malformation (BAV; (3M, 2F, 65±13yr) as well as normal aorta from organ donor subjects (3M, 2F 40±11yr). MFS and BAV tissue showed co-localisation of TGFβ1–3 and Smad3 in myofibroblasts, vascular smooth muscle cells (VSMCs) and chronic inflammatory cells in the subintimal layer and tunica media and in fibroblasts in tunica adventitia. In normal aortic wall there was minimal TGFβ and Smad3 staining. Cultured VSMCs (passage 1–5) from MFS and BAV showed nuclear Smad3 and strong cytoplasmic TGFβ1–3 expression in numerous vesicles and in areas of exocytosis and extracellular localisation. In control cells there was much weaker TGFβ1–3 staining compared to aneurysm derived cells. Smad3 staining in normal cells was located in the cytoplasm alone. Compared to normal tissue and cells AngII receptor type1 and 2 (ATR1 and 2) expression was increased in both aneurysm tissue and in cultured VSMCs derived from aneurysm. Cultured VSMCs were treated for 48h with the ATR1 antagonist losartan (10μM). This caused disappearance of TGFβ1–3 vesicle localisation and nuclear expression of Smad3. The findings of increased TGFβ1–3 and Smad3 expression in aneurysm tissue and cultured cells are consistent with aberrant TGFβ signalling and with activation of the Smad3 signalling pathway. Furthermore reduction in extracellular TGFβ and de-activation of Smad3 expression associated with losartan treatment supports a role for ATR1 antagonism in inhibition of aneurysm progression. Figure 1: Risk of IMH Conversion to Typical Dissection

MESSENGER RNA EXPRESSION OF ANGIOTENSIN II AND TRANSFORMING GROWTH FACTOR BETA 1 (TGFβ1) IN KIDNEY TRANSPLANTED PATIENTS.

2000 ◽  
Vol 69 (Supplement) ◽  
pp. S400
Author(s):  
Valeria R. Mas ◽  
Teresita R. Alvarellos ◽  
Susana M. Albano ◽  
Carlos R. Chiurchiu ◽  
Constancio A. Giraudo ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Messenger Rna ◽  
Transforming Growth Factor ◽  
Rna Expression ◽  
Growth Factor Beta
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