Using potentially novel mouse models, we demonstrate here that the expression of miR-150 is higher in CMs than other myocardial cells, and conditional CM-specific miR-150 KO (miR-150 cKO) mice enhance cardiac dysfunction, stress, fibrosis, and apoptosis after MI without affecting mortality; transcriptome profiling in miR-150 cKO mice identifies Sprr1a as a direct and functional target of CM miR-150; and the hearts of Sprr1a-hypomorphic mice are protected against MI. The gene discussed is SPRR1A; the disease is myocardial infarction.