Tumor Extracellular Vesicles Aggravate Mitochondrial Damage in Myocardial Ischemia/Reperfusion Injury

Abstract Cancer patients have a higher risk of all types of cardiovascular diseases (CVDs). Cardiologists are encountering a growing number of cancer patients with CVDs, and an increasing number of cancer patients undergoing percutaneous coronary intervention (PCI). The mechanistic link between cancer and CVDs remains elusive. Here, the meta‐analysis shows the increased incidence ratio of all‐cause mortality and cardiovascular (CV) mortality in patients undergoing PCI with cancer compared with non‐cancer. We experimentally demonstrated that cancer aggravated mitochondrial dysfunction and myocardial ischemia/reperfusion (I/R) injury in two models of lung cancer in mice. Plasma extracellular vesicles (EVs) derived from cancer mice exacerbated cardiac I/R injury in vivo and in vitro, while inhibition of tumor EVs secretion by lipid‐coated polyacrylic acid/calcium phosphate nanoparticles delivered a neutral sphingomyelinase inhibitor (GW4869) showed the opposite results. Lung‐specific miR‐485‐3p sponges mediated by Adeno‐associated virus 6 suppress cardiac damage and mitochondrial dysfunction in CC10‐KRAS^G12D mice post‐I/R. Mechanistically, PPARGC1A/PGC‐1α is post‐transcriptionally repressed by miR‐485‐3p in cardiomyocytes, leading to the inhibition of mitochondrial complex I subunits and ATP synthesis. Taken together, our findings reveal for the first time that cancer can aggravate cardiac injury and mitochondrial dysfunction by releasing miR‐485‐3p‐enriched extracellular vesicles derived from cancer cells.