Transcriptomic profiling of Adcy7-knockout bone marrow-derived macrophages

Myocardial ischemia/reperfusion (I/R) injury remarkably thwarts the therapeutic efficiency of percutaneous coronary intervention for myocardial ischemia disorders, and cardiac macrophages have been shown to play critical roles during the injury process. Here, we identified adenylyl cyclase 7 (ADCY7) in macrophage as a critical candidate for I/R injury based on spatial transcriptomics analysis and multi-parameter flow cytometry and confirmed the expression changes in I/R injury mouse model and patients with myocardial infarction. Taking advantage of depletion/reconstitution of macrophages in male mice, we demonstrated that macrophage Adcy7 deficiency significantly exacerbated myocardial I/R injury and impaired cardiac function, while Adcy7 overexpression attenuated these pathological manifestations. Notably, we observed that macrophage Adcy7 deficiency led to more infiltration of leukocytes and production of pro-inflammatory cytokines. To gain insight into how ADCY7 regulates inflammation, we performed transcriptomic and phosphor-proteomic analysis on Adcy7-deficient bone marrow-derived macrophages, and found that ADCY7 induced protein kinase A activation, leading to inhibition of nuclear translocation of NF-κB, thus restraining pro-inflammatory response. We further developed photoactivated adenylyl cyclase activation system combined with the macrophage depletion/reconstitution procedure and achieved substantial effect to alleviate cardiac inflammation and myocardial I/R injury. Together, our study identified ADCY7 as a promising therapeutic target for developing effective anti-inflammatory strategy to ameliorate myocardial I/R injury.