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Published on: June 3, 2018
Sipa1 Drives a Maladaptive Fibroblast-Myeloid Axis After Myocardial Infarction
Seien Ko1, Xueyuan Liu1, Yurika Taniguchi1
1Department of Cardiology (S.K., X.L., Y.T., G.I., J.K., H.Y., K.S., H.H., Y.K., J.E., M.S., A.A., M.I.), Keio University School of Medicine, Tokyo, Japan.
Background:
Sipa1 (signal-induced proliferation-associated gene 1) is known as a specific Rap1 (Ras-related protein 1) GTPase-activating protein that negatively regulates Rap1 signaling. Although Sipa1 has been extensively studied in cancer research, its role in the wound-healing response after myocardial infarction (MI) remains unexplored.
Methods:
To investigate the role of endogenous Sipa1 in MI, we performed permanent left anterior descending artery ligation in both Sipa1 knockout mice and their control littermates. Bone marrow transplantation, flow cytometry, cell sorting, and transcriptomic analysis were conducted to identify the cellular source of Sipa1 in the infarcted heart. The role of cardiac fibroblast-derived Sipa1 during MI was examined using Sipa1 deletion approaches, specifically in cardiac fibroblasts, in vivo and in vitro.
Results:
Mice deficient in Sipa1 exhibited improved post-MI survival and cardiac function, along with attenuated expression of inflammatory mediators and diminished accumulation of Ly6C (lymphocyte antigen 6 complex, locus C)high monocytes and CCR (C-C chemokine receptor) 2+ macrophages in the infarcted heart. Although Sipa1 was broadly expressed in the heart, cardiac fibroblasts were responsible for the Sipa1-induced deleterious phenotype as demonstrated by cardiac fibroblast-specific Sipa1 conditional knockout mice, which averted excessive inflammation and adverse cardiac remodeling following MI. Mechanistically, Sipa1 promotes the production of CCL (C-C chemokine ligand) 2, CCL7, and GM-CSF (granulocyte/macrophage colony-stimulating factor) in the cardiac fibroblasts early after MI via a noncanonical RasGRP2 (Ras guanine nucleotide-releasing protein 2)-Ras-JNK (cellular Jun N-terminal kinase) signaling pathway, irrespective of canonical Rap1, thereby facilitating the accumulation and activation of inflammatory monocytes and macrophages.
Conclusions:
These results identify a previously unknown fibroblast-myeloid axis characterized by Sipa1, which initiates excessive inflammation and leads to poor outcomes after MI. Targeting Sipa1 offers a potential novel therapeutic strategy to optimize post-MI wound-healing response, thereby preventing the development of chronic ischemic heart failure.
Insights
Signal-induced proliferation-associated gene 1 (Sipa1) in cardiac fibroblasts drives inflammation after myocardial infarction (MI). Inhibiting Sipa1 improves heart function and survival post-MI, offering a new therapeutic target for heart failure.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Signal-induced proliferation-associated gene 1 (Sipa1) is a Rap1 GTPase-activating protein that negatively regulates Rap1 signaling.
- While studied in cancer, Sipa1's role in myocardial infarction (MI) wound healing is unknown.
Purpose of the Study:
- To investigate the role of endogenous Sipa1 in the cardiac response to MI.
- To identify the cellular source and mechanism of Sipa1's action in infarcted hearts.
Main Methods:
- Used Sipa1 knockout mice and cardiac fibroblast-specific conditional knockouts.
- Employed bone marrow transplantation, flow cytometry, and transcriptomic analysis.
- Investigated Sipa1's role in vitro and in vivo in cardiac fibroblasts.
Main Results:
- Sipa1 deficiency improved post-MI survival and cardiac function, reducing inflammation and immune cell infiltration.
- Cardiac fibroblasts were identified as the primary source of Sipa1, driving adverse outcomes.
- Sipa1 in fibroblasts promoted chemokine production via a RasGRP2-Ras-JNK pathway, enhancing inflammatory cell accumulation.
Conclusions:
- A novel Sipa1-mediated fibroblast-myeloid axis exacerbates inflammation post-MI.
- Targeting Sipa1 presents a potential therapeutic strategy to improve wound healing and prevent heart failure after MI.
