CTRP9 Ameliorates Atrial Inflammation, Fibrosis, and Vulnerability to Atrial Fibrillation in Post‐Myocardial Infarction Rats

Abstract

Background Inflammation and fibrosis play an important role in the pathogenesis of atrial fibrillation ( AF ) after myocardial infarction ( MI ). CTRP9 (C1q/tumor necrosis factor‐related protein‐9) as a secreted glycoprotein can reverse left ventricle remodeling post‐ MI , but its effects on MI ‐induced atrial inflammation, fibrosis, and associated AF are unknown. Methods and Results MI model rats received adenoviral supplementation of CTRP 9 (Ad‐ CTRP 9) by jugular‐vein injection. Cardiac function, inflammatory, and fibrotic indexes and related signaling pathways, electrophysiological properties, and AF inducibility of atria in vivo and ex vivo were detected in 3 or 7 days after MI . shCTRP9 (short hairpin CTRP9) and sh RNA were injected into rat and performed similar detection at day 5 or 10. Adverse atrial inflammation and fibrosis, cardiac dysfunction were induced in both MI and Ad‐GFP (adenovirus‐encoding green fluorescent protein)+ MI rats. Systemic CTRP 9 treatment improved cardiac dysfunction post‐ MI . CTRP 9 markedly ameliorated macrophage infiltration and attenuated the inflammatory responses by downregulating interleukin‐1β and interleukin‐6, and upregulating interleukin‐10, in 3 days post‐ MI ; depressed left atrial fibrosis by decreasing the expressions of collagen types I and III , α‐ SMA , and transforming growth factor β1 in 7 days post‐ MI possibly through depressing the Toll‐like receptor 4/nuclear factor‐κB and Smad2/3 signaling pathways. Electrophysiologic recordings showed that increased AF inducibility and duration, and prolongation of interatrial conduction time induced by MI were attenuated by CTRP 9; moreover, CTRP 9 was negatively correlated with interleukin‐1β and AF duration. Downregulation of CTRP 9 aggravated atrial inflammation, fibrosis, susceptibility of AF and prolonged interatrial conduction time, without affecting cardiac function. Conclusions CTRP 9 is effective at attenuating atrial inflammation and fibrosis, possibly via its inhibitory effects on the Toll‐like receptor 4/nuclear factor‐κB and Smad2/3 signaling pathways, and may be an original upstream therapy for AF in early phase of MI .