Exosomes mediated fibrogenesis in dilated cardiomyopathy through a MicroRNA pathway
Xuebin Fu1,2, Rachana Mishra1,2, Ling Chen1,2
1Department of Cardiovascular-Thoracic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Insights
Familial dilated cardiomyopathy (DCM) cardiac exosomes promote fibrosis by upregulating miRNA-218-5p. This mechanism highlights a new pathway in DCM pathogenesis and cardiac fibrosis development.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Biology
Background:
- Cardiac fibrosis is a key feature of advanced familial dilated cardiomyopathy (DCM).
- The mechanisms driving cardiac fibrosis in DCM are not fully understood.
- Cardiac exosomes (Exos) have been implicated in fibrosis in other heart conditions.
Purpose of the Study:
- To investigate if exosomes secreted by familial DCM cardiomyocytes contribute to cardiac fibrosis.
- To elucidate the molecular mechanisms by which DCM-derived exosomes promote fibrogenesis.
Main Methods:
- Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from DCM and control (CTL) patients were cultured.
- Exosomes were isolated from conditioned media of angiotensin II-stimulated hiPSC-CMs.
- Cardiac fibroblasts were exposed to DCM-Exos and CTL-Exos in vitro.
- DCM-Exos were injected into mouse hearts to assess in vivo effects.
- Molecular mechanisms involving miRNA-218-5p and TGF-β signaling were analyzed.
Main Results:
- Exposure to DCM-Exos, but not CTL-Exos, increased fibrogenesis in cultured cardiac fibroblasts.
- In vivo injection of DCM-Exos led to enhanced cardiac fibrosis and impaired cardiac function in mice.
- Upregulation of miRNA-218-5p was identified within DCM-Exos.
- MiRNA-218-5p promoted fibrogenesis by suppressing TNFAIP3, a key inflammation inhibitor, thereby activating TGF-β signaling.
Conclusions:
- Cardiomyocyte-derived exosomes from familial DCM patients exert a profibrotic effect.
- MiRNA-218-5p within these exosomes is a critical mediator of cardiac fibrosis in DCM.
- This study reveals a novel pathogenic pathway involving exosomes in the development of cardiac fibrosis in DCM.
Abstract:
Cardiac fibrosis is a hallmark in late-stage familial dilated cardiomyopathy (DCM) patients, although the underlying mechanism remains elusive. Cardiac exosomes (Exos) have been reported relating to fibrosis in ischemic cardiomyopathy. Thus, we investigated whether Exos secreted from the familial DCM cardiomyocytes could promote fibrogenesis. Using human iPSCs differentiated cardiomyocytes we isolated Exos of angiotensin II stimulation conditioned media from either DCM or control (CTL) cardiomyocytes. Of interest, cultured cardiac fibroblasts had increased fibrogenesis following exposure to DCM-Exos rather than CTL-Exos. Meanwhile, injecting DCM-Exos into mouse hearts enhanced cardiac fibrosis and impaired cardiac function. Mechanistically, we identified the upregulation of miRNA-218-5p in the DCM-Exos as a critical contributor to fibrogenesis. MiRNA-218-5p activated TGF-β signaling via suppression of TNFAIP3, a master inflammation inhibitor. In conclusion, our results illustrate a profibrotic effect of cardiomyocytes-derived Exos that highlights an additional pathogenesis pathway for cardiac fibrosis in DCM.
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