Knockdown of TSP-4 alleviates MI/RI-induced myocardial injury and improves brain inflammation by enhancing blood–brain barrier stability

Myocardial ischemia-reperfusion injury (MI/RI) not only affects cardiac function but also has significant implications for neurological health, potentially leading to cognitive and behavioral impairments. At present, the regulatory role of thrombospondin-4 (TSP-4) in MI/RI has not been reported. A MI/RI mouse model was constructed, and primary cardiomyocytes were isolated. An MI/RI in vitro cell model was constructed using hypoxia/reoxygenation (H/R)-induced H9c2 cells. Haematoxylin and eosin and Masson staining were performed to observe morphological differentiation and fibrosis in myocardial tissues. Evans blue staining was used to analyse blood-brain barrier (BBB) permeability. Behavioural experiments were conducted to assess the learning and cognitive functions of mice. The results showed that the expression of TSP-4 was significantly increased in the blood of patients with ischemic cardiomyopathy and in the myocardial tissue of MI/RI mice. Functional studies showed that TSP knockdown alleviated H/R-induced H9c2 cell injury, including inflammation and oxidative stress. Importantly, interference with TSP-4 alleviated myocardial dysfunction in MI/RI mice. Mechanistically, by improving BBB stability, TSP-4 knockdown alleviated neuronal injury and the inflammatory response in mice induced by MI/RI. Further research found that silencing TSP-4 alleviated cognitive impairment and improved learning in MI/RI mice. Knockdown of TSP-4 improved MI/RI-induced functional cardiomyocyte injury. In addition, by enhancing BBB stability, TSP-4 silencing alleviated MI/RI-induced neurological injury and cognitive impairment in mice.