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Cardiomyocyte apoptosis is known to contribute to myocardial ischemia/reperfusion (I/R) injury. Caspase recruitment domain-containing protein 9 (CARD9) play a role in cardiac fibrosis and dysfunction. However, the role of CARD9 in apoptosis of cardiomyocytes in myocardial I/R injury and its underlying mechanisms are still unclear. In this study, CARD9 expression was found to increase in H9c2 cells in response to hydrogen peroxide. Loss of CARD9 significantly increased caspase-3 activation and cardiomyocyte death following oxidative stress in vitro. Conversely, CARD9 overexpression decreased apoptosis as evidenced by a reduction in caspase-3 activation and the apoptotic rate. The caspase recruitment domain (CARD) of CARD9 was necessary for the protective effect of CARD9 against oxidative stress in cardiomyocytes. CARD9 suppressed the activation of caspase-9 by interacting with Apaf-1 via its CARD domain in H9c2 cells exposed to H 2 O 2. Ablation of caspase-9 activity by z-lehd-fmk effectively prevented the detrimental effect of CARD9 deficiency on cardiomyocytes. Wild-type (WT) and CARD9−/− mice were subjected to 30 min of left ascending coronary (LAD) ischemia and 12 h of reperfusion. TdT-mediated dUTP nick end labeling (TUNEL) staining analysis showed that CARD9−/− mice exhibited a significantly higher number of apoptotic-positive cells after myocardial I/R injury than the WT mice. These results suggest that CARD9 protects cardiomyocytes from apoptosis by interacting with Apaf-1 and interfering with apoptosome formation following myocardial I/R injury in vivo and in vitro. Image 1 • CARD9 overexpression protects cardiomyocytes from apoptosis-induced by H 2 O 2. • CARD9 deficiency aggravates cardiomyocyte apoptosis following myocardial I/R injury. • CARD9 is involved in regulating cardiomyocyte apoptosis by interacting with Apaf-1. [ABSTRACT FROM AUTHOR]