Plasma Proteomic Profiling Reveals ITGA2B as A Key Regulator of Heart Health in High-altitude Settlers.

Myocardial injury is a common disease in the plateau, especially in the lowlanders who have migrated to the plateau, in which the pathogenesis is not well understood. Here, we established a cohort of lowlanders comprising individuals from both low-altitude and high-altitude areas and conducted plasma proteome profiling. Proteomic data showed that there was a significant shift in energy metabolism and inflammatory response in individuals with myocardial abnormalities at high altitude. Notably, integrin ITGA2B emerged as a potential key player in this context. Functional studies demonstrated that ITGA2B upregulated the transcription and secretion of interleukin-6 (IL-6) through integrin-linked kinase (ILK) and nuclear factor-κB (NF-κB) signaling axis under hypoxic conditions. Moreover, ITGA2B disrupted mitochondrial structure and function, increased glycolytic capacity, and aggravated energy reprogramming from oxidative phosphorylation to glycolysis. Leveraging the therapeutic potential of traditional Chinese medicine in cardiac diseases, we discovered that tanshinone ⅡA (TanⅡA) effectively alleviated the high-altitude myocardial injury caused by the abnormally elevated expression of ITGA2B, thus providing a novel candidate therapeutic strategy for the prevention and treatment of high-altitude myocardial injury.