Myocardial microRNAs (myo-miRs) are released into the circulation after acute myocardial infarction (AMI). How they impact remote organs is however largely unknown. Here we show that circulating myo-miRs are carried in exosomes and mediate functional crosstalk between the ischemic heart and the bone marrow (BM). In mice, we find that AMI is accompanied by an increase in circulating levels of myo-miRs, with miR-1, 208, and 499 predominantly in circulating exosomes and miR-133 in the non-exosomal component. Myo-miRs are imported selectively to peripheral organs and preferentially to the BM. Exosomes mediate the transfer of myo-miRs to BM mononuclear cells (MNCs), where myo-miRs downregulate CXCR4 expression. Injection of exosomes isolated from AMI mice into wild-type mice downregulates CXCR4 expression in BM-MNCs and increases the number of circulating progenitor cells. Thus, we propose that myo-miRs carried in circulating exosomes allow a systemic response to cardiac injury that may be leveraged for cardiac repair.

Myocardial fibrosis involves the loss of cardiomyocytes, myocardial fibroblast proliferation, and a reduction in angiogenesis, ultimately leading to heart failure, Given its significant implications, it is crucial to explore novel therapies for myocardial fibrosis. Recently one emerging avenue has been the use of small extracellular vesicles (sEV)-carried miRNA. In this review, we summarize the regulatory role of sEV-carried miRNA in myocardial fibrosis. We explored not only the potential diagnostic value of circulating miRNA as biomarkers for heart disease but also the therapeutic implications of sEV-carried miRNA derived from various cellular sources and applications of modified sEV. This exploration is paramount for researchers striving to develop innovative, cell-free therapies as potential drug candidates for the management of myocardial fibrosis.

Small extracellular vesicles (sEVs) are membrane‐bound nanoparticles released by cells for intercellular or inter‐tissue communication and play key roles in multiple cardiovascular disorders. However, the mechanisms underlying sEV‐mediated myocardial fibrosis in hypertrophic cardiomyopathy (HCM) are not well understood. In this study, it is discovered that the levels of miR‐15a‐5p and miR‐96‐5p in circulating sEVs ( ^sEV miR‐15a‐5p/96‐5p) are elevated in HCM patients with myocardial fibrosis. These sEVs enhance fibroblast proliferation and differentiation in vitro. Similar findings are observed in isopropanol (ISO)‐induced myocardial fibrosis mouse model, where ^sEV miR‐15a‐5p/96‐5p levels are elevated, predominantly originating from lung‐derived sEVs. GW4869‐mediated sEV suppression reduces pulmonary/cardiac ^sEV miR‐15a‐5p/96‐5p levels, suggesting therapeutic potential. Importantly, the systemic trafficking of lung‐derived sEVs is also mapped to cardiac tissue in vivo using a lung‐specific lineage‐tracing strategy using SFTPC (surfactant protein C) promoter‐driven AAV9‐CD63‐GFP vectors. Administering lung‐derived sEVs from ISO‐treated mice into the myocardium increases cardiac fibroblast proliferation and scar formation. Furthermore, it is identified that miR‐15a‐5p and miR‐96‐5p directly target Smad7 , reducing its expression, while SMAD7 overexpression reverses profibrotic effects. These findings indicate that lung‐derived ^sEV miR‐15a‐5p/96‐5p may exacerbate myocardial fibrosis by targeting Smad7 in cardiac fibroblasts. Thus, lung‐derived sEV miR‐15a‐5p and miR‐96‐5p can serve as novel biomarkers and therapeutic targets for managing HCM‐related myocardial fibrosis.

Cardiovascular disease remains the leading global cause of death. Pathological cardiac hypertrophy is a key precursor to heart failure (HF), a condition with high morbidity and mortality. Extracellular vesicles (EVs) have emerged as crucial mediators of intercellular communication, carrying bioactive cargoes that reflect cellular state and influence recipient cell function. This review provides a focused and integrative perspective distinct from broader overviews, by dissecting the dynamic, cell-type-specific roles of EVs across the continuum from pathological hypertrophy to overt HF. We critically synthesize evidence on how EVs derived from cardiomyocytes, fibroblasts, immune cells, and adipocytes orchestrate maladaptive remodeling. Furthermore, we evaluate their dual utility as emerging diagnostic biomarkers and as engineerable therapeutic vectors. By highlighting recent advances in EV engineering for targeted delivery and discussing persistent translational challenges, this article offers a unique mechanistic-to-translational viewpoint aimed at advancing the therapeutic application of EVs in cardiovascular medicine.

CXCR4 is a seven‑transmembrane‑spanning Gi‑coupled receptor for the SDF‑1 chemokine and plays a critical role in cardiovascular development and post‑injury repair. However, the specific role of CXCR4 in cardiomyocytes is incompletely understood. It was hypothesized that CXCR4 activation in cardiomyocytes antagonizes β‑adrenoceptor/Gs signaling‑induced cardiac dysfunction. Cardiomyocyte‑specific CXCR4 knockout (CXCR4‑^CMKO) mice were generated by crossing CXCR4^fl/fl and MHC‑Cre^+/‑ mice. Their cardiac structure and function in the basal state are equivalent to that of the control MHC‑Cre^+/‑ littermates until at least 4 months old. However, following continuous subcutaneous administration of isoproterenol (Iso) via an osmotic mini‑pump, the ventricular myocardial contractility, dilation, cardiomyocyte apoptosis, and interstitial fibrosis are worse in CXCR4‑^CMKO mice than in MHC‑Cre^+/‑ littermates. In the cultured H9C2 cardiomyocytes, SDF‑1 treatment markedly attenuated Iso‑induced apoptosis and reduction in phospho‑Akt, and this protective effect was lost by knockdown of CXCR4 or by co‑treatment with Gi inhibitors. In conclusion, CXCR4 promotes cardiomyocyte survival and heart function during β‑adrenergic stress.