Abstract

Atrial fibrillation (AF) affects >30 million individuals worldwide. However, no genetic mutation from human patients with AF has been linked to inflammation. Here, we show that AF‐associated human variant p.Ile138Thr in natriuretic peptide A (NPPA) encoding the atrial natriuretic peptide (ANP) causes inflammation, fibroblast activation, atrial fibrosis, and AF in knock‐in (KI) rats. Variant p.Ile138Thr inhibits the interaction between ANP and its receptor natriuretic peptide receptor A and reduces intracellular cGMP levels. RNA sequencing and follow‐up analyses showed that mutant ANP (mANP) activates multiple innate immunity pathways, including TNF‐α, NF‐κB, and IL‐1β signaling. mANP induces differentiation of cardiac fibroblasts (CFs) to myofibroblasts and promotes CF proliferation and fibrosis. These results suggest that NPPA variant p.Ile138Thr causes AF by activating TNF‐α, NF‐κB, and IL‐1β signaling …

Date

2019

Authors

Chen Cheng, Huixia Liu, Chengcheng Tan, Doudou Tong, Yongxuan Zhao, Xia Liu, Wenxia Si, Liniin Wang, Lina Liang, Jia Li, Chenghui Wang, Qiuyun Chen, Yimei Du, Qing K Wang, Xiang Ren

Journal

The FASEB Journal

Volume

33

Issue

8

Pages

8878-8891

Publisher

Federation of American Societies for Experimental Biology