We investigated the impact of both BMP9 deficiency and replenishment on the pathogenesis of MI in mice. Our results showed an aggravated pathological phenotype of MI in BMP9 knockout (KO) mice, which can be alleviated by replenishment of BMP9. Therefore, we further investigated the mechanism whereby BMP9 protects against MI-induced cardiac damage and dysfunction via its multiple actions among the liver, lymph, and heart.