SASP-mediated cellular senescence following myocardial infarction: from spatiotemporal immune regulation to therapeutic strategies

Currently, the primary causes of death following myocardial infarction include sudden cardiac death, malignant arrhythmias, and acute heart failure, all resulting from myocardial necrosis caused by coronary artery occlusion. Due to population aging and lifestyle changes, the global number of patients with myocardial infarction is expected to continue to rise. Cellular senescence refers to the permanent arrest of cell proliferation in response to stress stimuli; it serves as a crucial tumor defense mechanism and is closely associated with tissue aging and chronic inflammation. The senescence-associated secretory phenotype (SASP) is one of the most characteristic features of senescent cells. Cardiac cells develop a SASP and secrete SASP factors in response to stimuli such as oxidative stress, DNA damage, and hypoxia, playing a key role in immune regulation and tissue repair following myocardial infarction. The SASP exhibits marked spatiotemporal heterogeneity following myocardial infarction: during the acute phase, it contributes to inflammatory amplification and immune cell recruitment; during the subacute phase, it is involved in inflammation resolution, matrix remodeling, and scar formation; and during the chronic phase, it promotes chronic inflammation, paracrine senescence, pathological fibrosis, and cardiac dysfunction. Spatially, the SASP influences scar stabilization in the infarct zone, inflammation-electrophysiological coupling in the border zone, and compensatory remodeling in the distal region. The sustained expression of the SASP is a major driver of adverse ventricular remodeling and excessive fibrosis following myocardial infarction. Therefore, targeting senescent cells and persistent, pathological SASP represents a highly promising therapeutic strategy in the field of cardiovascular regenerative medicine. This review will discuss senescence in different cell types following myocardial infarction, the spatiotemporal heterogeneity of the immune response mediated by the SASP after myocardial infarction, and the immune cells regulated by the SASP.