MFAP4 deletion attenuates the progression of angiotensin II-induced atrial fibrosis and atrial fibrillation

Europace. 2022 Feb 2;24(2):340-347. doi: 10.1093/europace/euab124.

Abstract

Aims: Microfibrillar-associated protein 4 (MFAP4) is associated with atrial fibrillation (AF). Nevertheless, the specific role and underlying mechanism of MFAP4 in atrial fibrosis, the hallmark of AF, remain undefined. This study aims to elucidate the role of MFAP4 in the regulation of atrial fibrosis and to explore the underlying mechanism.

Methods and results: This study used MFAP4 knockout (MFAP4-KO) mice and their wild-type (WT) littermates to investigate the effect of angiotensin II (Ang II) (2000 ng/kg/min for 3 weeks) on atrial fibrosis and susceptibility to AF in terms of morphology, histology, electrophysiology, and molecular biology. MFAP4 deletion in mice did not alter cardiac structure and function at baseline. After treatment with Ang II, the MFAP4-KO mice showed a decreased left atrial enlargement and fibrosis, slowed atrial conduction, and reduced susceptibility to AF compared with the WT mice. Regarding the mechanism, we found that MFAP4 deletion markedly inhibited activated focal adhesion kinase (FAK)-mediated PI3K-AKT signalling and MEK1/2-ERK1/2 signalling after Ang II treatment.

Conclusions: Overall, our study showed that loss of MFAP4 attenuates Ang II-mediated left atrial fibrosis and dilation and decreases susceptibility to AF by decreasing the phosphorylation of FAK and inhibiting the activation of the PI3K-AKT and MEK1/2-ERK1/2 signalling pathways. These findings further indicate that targeting MFAP4 may be a potential upstream therapeutic option for atrial fibrosis and AF.

Keywords: Angiotensin II; Atrial fibrillation; Fibrosis; MFAP4; Signalling pathway.

MeSH terms

  • Angiotensin II* / adverse effects
  • Angiotensin II* / metabolism
  • Animals
  • Atrial Fibrillation* / drug therapy
  • Fibrosis
  • Heart Atria
  • Humans
  • Mice
  • Phosphatidylinositol 3-Kinases / adverse effects
  • Phosphatidylinositol 3-Kinases / metabolism

Substances

  • Angiotensin II