Mfap4, or Microfibrillar-associated protein 4, is an extracellular matrix (ECM) protein belonging to the fibrinogen-related domain superfamily. It is highly expressed in elastin-rich tissues and is involved in ECM organization, regulating proper elastic fiber assembly. It also interacts with RGD-dependent integrin receptors, participating in integrin signaling pathways [1].

In KO mouse models, Mfap4 deficiency attenuates angiotensin II-induced atrial fibrosis and atrial fibrillation by inhibiting activated focal adhesion kinase (FAK)-mediated PI3K-AKT and MEK1/2-ERK1/2 signalling [2]. In the context of abdominal aortic aneurysm (AAA), ApoE -/- Mfap4 -/- mice show lower AAA incidence, reduced macrophage infiltration, and decreased matrix metalloproteinase activity [3]. In renal fibrosis, MFAP4 -/- mice subjected to unilateral ureteral obstruction exhibit decreased NF-κB and TGF-β/Smad pathway activation and reduced ECM deposition [5]. Also, Mfap4 -/- mice show delayed neointimal formation after carotid artery ligation, with decreased VSMC proliferation and monocyte chemotaxis [4].

In summary, Mfap4 plays essential roles in elastic fiber homeostasis and integrin signaling. Through gene-knockout mouse models, its contributions to diseases such as atrial fibrillation, AAA, renal fibrosis, and neointimal hyperplasia have been revealed. These findings suggest that targeting Mfap4 could be a potential therapeutic approach for these disease areas.

References:

1. Mohammadi, Ali, Sorensen, Grith L, Pilecki, Bartosz. 2022. MFAP4-Mediated Effects in Elastic Fiber Homeostasis, Integrin Signaling and Cancer, and Its Role in Teleost Fish. In Cells, 11, . doi:10.3390/cells11132115. https://pubmed.ncbi.nlm.nih.gov/35805199/

2. Wang, Huibo, Liu, Mingxin, Wang, Xixing, Shuai, Wei, Fu, Hui. . MFAP4 deletion attenuates the progression of angiotensin II-induced atrial fibrosis and atrial fibrillation. In Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, 24, 340-347. doi:10.1093/europace/euab124. https://pubmed.ncbi.nlm.nih.gov/34379753/

3. Pilecki, Bartosz, de Carvalho, Paulo V S D, Kirketerp-Møller, Katrine L, Lindholt, Jes S, Sorensen, Grith L. 2021. MFAP4 Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation Through Regulation of Macrophage Infiltration and Activity. In Frontiers in cardiovascular medicine, 8, 764337. doi:10.3389/fcvm.2021.764337. https://pubmed.ncbi.nlm.nih.gov/34805319/

4. Schlosser, Anders, Pilecki, Bartosz, Hemstra, Line E, Holmskov, Uffe, Sorensen, Grith L. 2015. MFAP4 Promotes Vascular Smooth Muscle Migration, Proliferation and Accelerates Neointima Formation. In Arteriosclerosis, thrombosis, and vascular biology, 36, 122-33. doi:10.1161/ATVBAHA.115.306672. https://pubmed.ncbi.nlm.nih.gov/26564819/

5. Pan, Zhou, Yang, Kang, Wang, Huibo, Bai, Tao, Zhu, Hengcheng. 2020. MFAP4 deficiency alleviates renal fibrosis through inhibition of NF-κB and TGF-β/Smad signaling pathways. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 34, 14250-14263. doi:10.1096/fj.202001026R. https://pubmed.ncbi.nlm.nih.gov/32905637/