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

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.

Identification and validation of key genes associated with atrial fibrillation in the elderly

“…MFAP4 , also known as MAGP -36 in some species, is produced by vascular smooth muscle cells and is highly enriched in the blood vessels of the heart and lungs, contributing to the structure and function of elastic fibers ( 51 , 52 ). MFAP4 is involved in cardiac remodeling and its deletion attenuates the progression of angiotensin II-induced atrial fibrosis and AF ( 53 ). In addition, MFAP4 is associated with aneurysms and peripheral arterial diseases ( 54 ).…”

MFAP4-Mediated Effects in Elastic Fiber Homeostasis, Integrin Signaling and Cancer, and Its Role in Teleost Fish

“…In the heart, MFAP4 was upregulated in a model of angiotensin II (Ang II)-induced atrial fibrillation, while MFAP4-deficient mice showed reduced atrial enlargement and fibrosis. Moreover, MFAP4 deficiency inhibited Ang II-induced activation of FAK, PI3K, AKT and ERK kinases [87], indicating that the observed effects were integrin-mediated. In another study, it was reported that in freshly isolated rat cardiac cells, MFAP4 expression was 40 times higher in cardiac fibroblasts than in cardiomyocytes.…”

Role and new insights of microfibrillar‐associated protein 4 in fibrotic diseases

“…Additionally, previous studies have indicated that focal adhesion kinase (FAK) and downstream signaling may play critical roles in the process of MFAP4 promoting cardiac fibrosis [89]. Activated FAK‐mediated PI3K‐AKT and MEK1/2‐ERK1/2 signaling pathways were inhibited by MFAP4 deletion after Ang II treatment, suggesting that the loss of MFAP4 is involved in attenuating Ang II‐mediated fibrosis and dilation of the left atrium [90]. Therefore, these relatively high levels of MFAP4 in different cardiac fibrotic diseases indicate that MFAP4 may play a pivotal role in the process of cardiac fibrosis.…”