Cardiac fibrosis is an integral part of many heart diseases. Characterized by an excessive deposition of the extracellular matrix (ECM) within cardiac interstitial spaces, it exacerbates the passive stiffness of the myocardium leading to progressive heart dysfunction. The condition culminates in fatal arrhythmias and heart failure (Hf). Under pathological stress and environmental stimulus, cardiac fibroblasts (CFs), a major cellular group in the heart responsible for ECM homeostasis, transition into myofibroblasts. This transition alters ECM production and degradation, thus advancing cardiac fibrosis. Given the lack of safe and effective treatment options, there is a need for novel modulatory agents and potential therapeutic targets to be identified for clinical intervention.
The Role of IgE and miR-486a-5p in Cardiac Fibrosis
Cardiac fibrosis is a key feature of cardiac remodeling and a marker for heart failure. Elevating levels of Immunoglobulin E (IgE) play a causal role in pathological cardiac remodeling. Although the precise mechanism by which IgE promotes cardiac fibrosis is yet to be fully elucidated, studies indicate that increasing IgE levels regulate miR-486a-5p and its downstream factors like Smad1, furthering pathological cardiac fibrosis. This new insight could serve as potential therapeutic targets for pathological cardiac fibrosis intervention. IgE, one of the five types of immunoglobulins, primarily functions in allergic reactions. Prior research has associated high IgE levels with several types of cardiovascular diseases, including aortic aneurysm, atherosclerosis, atherosclerotic cardiovascular diseases (ASCVD), and cardiac insufficiency. Additionally, studies have uncovered the significant role of IgE and its high-affinity receptor (Fc, ε, R1) in promoting cardiac interstitial fibrosis and ventricular remodeling.
Fig 1. IgE alters miRNAs profile in CFs and down-regulates miR-486a-5p.1
The Mechanism of Fibroblast Activation and Fibrosis
The molecular mechanism of myofibroblast activation and fibrosis is complex, encompassing numerous humoral factors such as the renin/angiotensin/aldosterone system, inflammatory and chemotactic factors, endothelin-1, and growth factors like TGF-β and platelet-derived growth factor (PDGF). Research has found that IgE can directly activate primary rat CFs, promote matrix protein production in a FcεR1-dependent manner, and that transforming growth factor-β is a key mediator in this process. Clear evidence has underscored the pivotal role of microRNAs (miRNAs) in regulating cardiac fibrosis. Some miRNAs, including miR-10a, miR-675, and miR-135a, have been shown to modulate the production of ECM by regulating TGF-β/SMAD signaling. Recently, it has been reported that IgE alters the expression spectrum of miRNA. Therefore, further investigation into the role of miRNAs in IgE-induced cardiac fibrosis and the specific role and molecular mechanism of CFS in IgE-induced cardiac fibrosis is warranted.
Unraveling the Potential Therapeutic Targets for Cardiac Fibrosis
Researchers have generated CF-specific FcεR1 gene knockout (KO) mice to ascertain the role of CFS in IgE-FcεR1 induced cardiac fibrosis. Unbiased miRNA deep sequencing analysis was conducted to explore the role of miRNAs in IgE-induced cardiac fibrosis. A novel signaling pathway (IgE/FcεR1/miR-486a-5p/Smad1) was identified that affects IgE-mediated CF activation both in vitro and in vivo. Additionally, the researchers established serum miR-486-5p levels' correlation with human heart failure. In summary, these findings propose IgE-FcεR1 and miR-486A-5P as new potential therapeutic targets for the treatment of cardiac fibrosis.
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Reference
- Zhao, Hongmei, et al. "Elevated IgE promotes cardiac fibrosis by suppressing miR-486a-5p." Theranostics 11.15 (2021): 7600.
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