Loss of myeloid differentiation protein 1 promotes atrial fibrillation in heart failure with preserved ejection fraction

Abstract

Aims Myeloid differentiation protein 1 (MD1) is expressed in the mammalian heart and exerts an anti-arrhythmic effect. Atrial fibrillation (AF) is closely related to heart failure with preserved ejection fraction (HFpEF). The potential impact of MD1 on AF vulnerability in an HFpEF model is not clear. Methods and results MD1 knock-out and wild-type (WT) mice were subjected to uninephrectomy and continuous saline or D-aldosterone infusion and given 1% sodium chloride drinking water for 4 weeks. Echocardiographic and haemodynamic measurements, electrophysiological studies, Masson staining, and molecular analysis were performed. Aldosterone-infused WT mice develop HFpEF with left ventricular hypertrophy, moderate hypertension, pulmonary congestion, and diastolic dysfunction. Aldosterone infusion increased the vulnerability of WT mice to AF, as shown by a prolonged interatrial conduction time, shortened effective refractory period, and higher incidence of AF. In addition, aldosterone infusion increased myocardial fibrosis and inflammation, decreased sarcoplasmic reticulum Ca 2+ -ATPase 2a protein expression and the phosphorylation of phospholamban at Thr17, and increased sodium/calcium exchanger 1 protein expression and the phosphorylation of ryanodine receptor 2 in WT mice. All of the above adverse effects of aldosterone infusion were further exacerbated in MD1 knock-out mice compare with WT mice. Mechanistically, MD1 deletion increased the activation of the toll-like receptor 4/calmodulindependent protein kinase II signalling pathway in in vivo and in vitro experiments. Conclusions MD1 deficiency increases the vulnerability of HFpEF mice to AF. This is mainly caused by aggravated maladaptive left atrial fibrosis and inflammation and worsened dysregulation of calcium handling, which is induced by the enhanced activation of the toll-like receptor 4/calmodulin-dependent protein kinase II signalling pathway.

Chronic low‐grade inflammation in heart failure with preserved ejection fraction

“…Moreover, calcium mishandling in left atrial cardiomyocytes of HFpEF rats was attenuated by administration of the anti‐inflammatory cytokine, IL‐10 (Bode et al, 2020 ). Atrial fibrillation has also been observed in a HFpEF model without obesity (Shuai et al, 2020 ). Uninephrectomy mice with continuous aldosterone and salt diet recapitulated some features of HFpEF, including AF (Shuai et al, 2020 ).…”

“…Atrial fibrillation has also been observed in a HFpEF model without obesity (Shuai et al, 2020 ). Uninephrectomy mice with continuous aldosterone and salt diet recapitulated some features of HFpEF, including AF (Shuai et al, 2020 ). Increased atrial fibrosis and AF inducibility occur along with elevated expression of TNFα, IL‐6, and IL‐1β (Shuai et al, 2020 ).…”

The Potential Role of RP105 in Regulation of Inflammation and Osteoclastogenesis During Inflammatory Diseases

“…These effects might regulate the bone niche or mechanical stimuli-induced physiological bone remodeling. Considered with the central role and high expression of RP105/MD-1 in adipose macrophages ( Watanabe et al, 2012 ), myocardial cells ( Shuai et al, 2020 ), cardiomyoblast cells ( Qin et al, 2019 ), and smooth muscle cells ( Wezel et al, 2016 ), this complex had been suggested as a possible therapeutic target in reducing chronic inflammatory of diabetes mellitus ( Watanabe et al, 2012 , 2013 ; Nagai et al, 2013 ), rheumatoid arthritis ( Bruhl et al, 2015 ), and SLE ( Yang et al, 2018a ).…”

“…Compared with wildtype mice, MD-1 knockout mice challenged with aldosterone infusion downregulate Ca 2+ -ATPase 2a (SERCA2a) expression and phospholamban phosphorylation at Thr17 (Shuai et al, 2020). In the MD-1 knockout mice, sodium/calcium exchanger 1 and phosphorylation of ryanodine receptor 2 expression resulted in increased myocardial fibrosis and inflammation, proving that MD-1 regulates the activation of the TLR4/CaMKII signaling in vivo and in vitro (Shuai et al, 2020). to H9c2 rat cardiomyoblasts to analyze the role of miR-141-3p and RP105 in myocardial ischemia.…”

“…The authors hypothesized that MD-1 deletion increases susceptibility to atrial fibrillation in heart failure with presented ejection fraction (HFpEJ) by enhancing the activation of TLR4/CaMKII signaling. Compared with wildtype mice, MD-1 knockout mice challenged with aldosterone infusion downregulate Ca 2+ -ATPase 2a (SERCA2a) expression and phospholamban phosphorylation at Thr17 ( Shuai et al, 2020 ). In the MD-1 knockout mice, sodium/calcium exchanger 1 and phosphorylation of ryanodine receptor 2 expression resulted in increased myocardial fibrosis and inflammation, proving that MD-1 regulates the activation of the TLR4/CaMKII signaling in vivo and in vitro ( Shuai et al, 2020 ).…”