Targeted therapies for myocardial infarction based on COPD-related extracellular vesicles

Chronic obstructive pulmonary disease (COPD) is a significant independent risk factor for myocardial infarction (MI), leading to impaired cardiac repair and poor prognosis. Small extracellular vesicles (sEVs), a key subtype of extracellular vesicles, are crucial mediators of inter-organ communication and may participate in harmful cardiopulmonary crosstalk. However, the net impact of COPD-context sEVs on post-MI injury and repair remains unclear. Here, we generated COPD-mimetic extracellular vesicles from cigarette smoke extract (CSE)-stimulated bronchial epithelial cells and investigated their effects and mechanisms in ischemic myocardial injury. COPD-mimetic extracellular vesicles (CSE-sEVs) were isolated from conditioned medium of CSE-stimulated BEAS-2B bronchial epithelial cells and characterized by transmission electron microscopy, nanoparticle tracking analysis, zeta potential measurement, and sEVs marker immunoblotting (CD63, CD81, TSG101). Cardiomyocyte injury models were treated with different graded sEVs doses in vitro, followed by assessment of cell viability, oxidative stress (SOD/MDA, ROS), inflammatory cytokines (IL-6, TNF-α, IL-1β), migration/invasion, mitochondrial membrane potential (JC-1), and apoptosis. Furthermore, MI mice received sEVs in vivo, and cardiac function and remodeling were evaluated by echocardiography and histology. Mechanistic dependency on PI3K/Akt signaling was tested using the selective inhibitor LY294002. COPD-related extracellular vesicles displayed canonical morphology, size distribution, and marker enrichment, with high colloidal stability. Extracellular vesicles treatment dose-dependently improved cardiomyocyte viability, suppressed ROS and pro-inflammatory cytokine release, restored mitochondrial membrane potential, and reduced apoptosis accompanied by downregulation of Bax/NF-κB/COX-2 and upregulation of Bcl-2. In MI mice, sEVs administration improved systolic function, attenuated ventricular dilation, mitigated myocardial injury, and reduced fibrotic remodeling. Pharmacologic blockade of PI3K/Akt with LY294002 substantially abrogated extracellular vesicles-mediated pro-survival, mitochondrial, anti-apoptotic, and antioxidant effects, supporting a PI3K/Akt-centered mechanism. COPD-mimetic sEVs confer robust cardioprotection after ischemic injury, in part by activating PI3K/Akt signaling to improve mitochondrial integrity while restraining NF-κB-linked inflammation, oxidative stress, and apoptosis. PI3K/Akt signaling contributes to, but may not fully account for, the observed effects.