Reparative Effects of VCAM-1 High-Performance MSC-derived Exosomes on Aged Diabetic Cardiomyocyte Injury: A Focus on Ferroptosis Suppression

Background: The cardiac dysfunction in elderly diabetes, resulting from the superimposition of age-related myocardial senescence and diabetes-induced myocardial injury, is difficult to intervene and lacks effective therapeutic strategies. Recent studies have revealed that ferroptosis may be a key mechanism underlying cardiomyocyte injury in diabetic cardiomyopathy. Mesenchymal stem cells (MSCs) and their secreted exosomes have shown potential in promoting cardiomyocyte repair, restoring cardiac function, improving insulin sensitivity, and mitigating diabetes-related complications. MSCs or their secreted exosomes may promote the repair of cardiomyocytes and the recovery of cardiac function, while also improving insulin sensitivity and alleviating the damage of diabetic complications. However, the mechanisms of actions of MSCs and -derived exosomes, as well as their relationship with ferroptosis, remain unclear. Methods: The model of high-glucose-damaged senescent cardiomyocytes was established by continuously culturing H9c2 cells or primary rat cardiomyocytes in a high-glucose condition, combined with H₂O₂ induction. And, the animal model of diabetic cardiomyopathy in aged rats was established by high-fat diet feeding combined with streptozotocin (STZ) administration, and followed keeping on high-fat diet. The cell model and animal model were administrated with VCAM-1⁺ MSCs derived exosomes, subsequently, the cell phenotypes, transcriptome sequencing, cardiac function, and the expression of genes related to senescence and ferroptosis were assessed. Results: In high-glucose-damaged senescent H9c2 cells and primary cardiomyocytes, as well as in myocardial tissues from rats with aged diabetic cardiomyopathy, mitochondrial damage, iron-ion accumulation, and reactive oxygen species (ROS) were significantly elevated, accompanied with weakened cardiac function and pronounced features of senescence and ferroptosis. After intervention with VCAM-1⁺ MSCs or their exosomes, the degree of cardiomyocyte injury, senescence, and ferroptosis was alleviated, leading to improved cardiac function. In injury senescent diabetic cardiomyocytes and myocardial tissue, Ras/Raf/MEK/ERK/c-FOS pathway was activated, while MSC-derived exosomes treatment significantly inhibited this pathway activation. Notably, the reparative effect of VCAM-1⁺ MSCs-derived exosomes on myocardial injury was superior to that of conventional MSCs-derived exosomes. Conclusion: Exosomes derived from VCAM-1 ⁺ MSCs attenuate cardiomyocyte ferroptosis via suppression of Ras/Raf/MEK/ERK/c-FOS pathway, thereby ameliorating myocardial injury resulting from superimposition of ageing-caused myocardial senescence and diabetes-induced myocardial damage in elderly diabetic cardiomyopathy.