Exosomally derived Y RNA fragment alleviates hypertrophic cardiomyopathy in transgenic mice

Abstract

Cardiosphere-derived cell exosomes (CDC exo ) and YF1, a CDC exo -derived non-coding RNA, elicit therapeutic bioactivity in models of myocardial infarction and hypertensive hypertrophy. Here we tested the hypothesis that YF1, a 56-nucleotide Y RNA fragment, could alleviate cardiomyocyte hypertrophy, inflammation, and fibrosis associated with hypertrophic cardiomyopathy (HCM) in transgenic mice harboring a clinically relevant mutation in cardiac troponin I (cTnI Gly146 ). By quantitative PCR, YF1 was detectable in bone marrow, spleen, liver, and heart 30 min after intravenous (i.v.) infusion. For efficacy studies, mice were randomly allocated to receive i.v. YF1 or vehicle, monitored for ambulatory and cardiac function, and sacrificed at 4 weeks. YF1 (but not vehicle) improved ambulation and reduced cardiac hypertrophy and fibrosis. In parallel, peripheral mobilization of neutrophils and proinflammatory monocytes was decreased, and fewer macrophages infiltrated the heart. RNA-sequencing of macrophages revealed that YF1 confers substantive and broad changes in gene expression, modulating pathways associated with immunological disease and inflammatory responses. Together, these data demonstrate that YF1 can reverse hypertrophic and fibrotic signaling pathways associated with HCM, while improving function, raising the prospect that YF1 may be a viable novel therapeutic candidate for HCM.

Risk Factors for Cardiovascular Disease

“…A recent study used transgenic mouse models with the cardiac troponin-I mutation (cTnI Gly146 ) to try to demonstrate that the exosomally derived Y-RNA fragment could regress the HCM clinic [163].…”

The potential roles of exosomes in pathological cardiomyocyte hypertrophy mechanisms and therapy: A review

“…Promotes cardiac hypertrophy [79,161,162] Adipocytes miR-200a Decreases TSC1 and activates mTOR, promoting cardiomyocyte hypertrophy [163] Cardiac fibroblast-induced pluripotent stem cells miR-22 May alter expression of miR-22, a key regulator of cardiac hypertrophy and remodeling [164] Cardiac progenitor cells miR-133a Protects hearts from pathological hypertrophy, fibrosis, and apoptosis [165] Cardiosphere-derived cells Y RNA fragment EV-YF1 Attenuates Ang II-induced cardiac hypertrophy; associated with changes in IL-10 expression [166,167] Spontaneously hypertensive rats (serum)…”

“…[166] Infusions of CDC-derived exosomes or the Y RNA fragment EV-YF1, a CDC-derived noncoding RNA, can attenuate angiotensin II-induced cardiac hypertrophy in association with changes in the expression of the anti-inflammatory cytokine IL-10. [166,167] These studies highlight the therapeutic potential of CDC-derived exosomes in mitigating pathological cardiac hypertrophy and promoting cardiac repair, further emphasizing the importance of stem cell-derived exosomes in this context.…”

Recent Advances of Using Exosomes as Diagnostic Markers and Targeting Carriers for Cardiovascular Disease

“…Poor cardiac retention limits the application of intravenous injection. After a series of modifications, exosomes can be designed as effective drug carriers to prepare drug preparations for cardiac repair or applied as tissue engineering approaches to improve their distribution in the heart. , Various exosome cargos encapsulated in novel formulations were designed for treating MI. Exosomes derived from dendritic cells and endothelial progenitor cells are also studied in preclinical research (Figure ).…”