Cardiac Myofibroblast‐Derived Small Extracellular Vesicles Moderate Fibrotic Responses via piRNA‐62788/PIWIL2‐Mediated SRF Silencing

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Abstract
During fibrogenesis, certain negative feedback loops are elicited to restrain persistent and hyperactive fibrotic responses. Activated fibroblasts have been found to acquire anti‐fibrotic phenotypes. However, the specific inhibitory modulators remain largely enigmatic. Thus, the present study aimed to examine the intrinsic autoregulatory mechanisms of fibroblasts. Here, we demonstrated that angiotensin II (AngII)‐primed cardiac myofibroblast moderated subsequent profibrotic activation. More importantly, this suppressive action was dependent on small extracellular vesicles (sEVs). Strikingly, small RNA sequencing identified an abundant presence of Piwi‐interacting RNAs (piRNAs) in sEVs. In cultured primary cardiac fibroblasts, piRNA‐62788 was induced by AngII receptor type 2 (AT 2 R) stimulation and encapsulated into sEVs. Furthermore, fibrogenic responses were attenuated by piRNA‐62788 overexpression, whereas aggravated by piRNA‐62788 knockdown. In a mouse model of transverse aortic constriction, either piRNA‐62788 agomir or circulating sEVs of patients with heart failure (HF) mitigated adverse cardiac remodelling, while piRNA‐62788 inhibitor‐containing sEVs accentuated myocardial fibrosis. Mechanistically, piRNA‐62788 formed a functional complex with PIWI‐like protein 2 (PIWIL2) and bound to the 3’ untranslated region (UTR) region of serum response factor ( Srf ) mRNA transcripts, leading to inhibition of the SRF signalling. Additionally, plasma sEV‐derived piRNA‐62788 was significantly upregulated in HF patients and negatively correlated with left ventricular ejection fraction. Collectively, we uncovered a protective negative feedback circuit controlled by AngII/AT 2 R/sEVs axis. Understanding this endogenous anti‐fibrotic pathway may hold therapeutic promise in HF.
Funding Information
  • National Natural Science Foundation of China (82070403)
  • National Natural Science Foundation of China (82270374)

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