Cardiovascular disease is one of leading causes of health hazards around the world, with acute myocardial infarction (AMI) ranking first in terms of disease burden (Alpert et al., 2000; Dauerman and Ibanez, 2021; Reed et al., 2017). AMI is exhibited as myocardial injuries due to lack of oxygen supply (Lim, 2017). Multiple studies of myocardial infarction have shown that myocardial structural disorders and dysfunction is regulated by the interplay between oxidative stress, inflammation, and apoptosis, which contribute to the progression of myocardial infarction-induced cardiac injuries (Bravo-San Pedro et al., 2017; Prabhu and Frangogiannis, 2016). Ischemic stress-induced cardiomyopathy mainly exhibits as cardiac remodeling, pathological hypertrophy, and life-threatening heart failure (Uriel et al., 2018). However, due to unsatisfactory therapeutic approaches, the rate of mortality is still higher after AMI. Therefore, it is necessary to identify novel drugs to combat the AMI-induced heart failure.

It is generally accepted that intense systemic and local inflammation exists after myocardial infarction (Wang et al., 2018; Zhang et al., 2022). The severity of the inflammatory response also determines the consequence of myocardial infarction, which mainly leads to pathological ventricular remodeling (Kologrivova et al., 2021; Toldo and Abbate, 2018). Cardiac remodeling after myocardial infarction depends on the balance of the individualized intensity of post-infarction inflammation and subsequent cardiac fibrosis (Granger and Kochar, 2018; Thackeray et al., 2018). Inflammation of myocardial infarction is initiated by immune cell infiltration for clearance of damaged cells, followed by a repair phase in which inflammation subsides myofibroblast proliferation and scar formation (Newby, 2019; Prabhu and Frangogiannis, 2016). Excessive inflammatory response can lead to sustained tissue damage and exacerbation of contractile dysfunction (Frangogiannis, 2014). Therefore, targeting cardiac inflammatory signaling appears to be a promising therapeutic approach for AMI patients. Notably, MAPK (mitogen-activated protein kinase) signaling pathways, composed by JNK (c-Jun N-Terminal Kinase), p38, and ERK (extracellular regulated protein kinase), have been reported to be associated with inflammatory phenotypes, and intervention of MAPK pathway may interfere with the onset and progression of inflammation(Shvedova et al., 2018; Zhang et al., 2022). Furthermore, the massive and rapid myocardial loss accompanied by cell necrosis or apoptosis after AMI activates a strong inflammatory response (Gupta et al., 2021; Zhang et al., 2022). Cardiac apoptosis also can be attenuated by modulating cardiac inflammatory signaling pathways (Ong et al., 2018). Therefore, anti-inflammation is one of effective therapeutic strategies for patients with myocardial infarction.

The compound (2E,6E)-2,6-bis(2-(trifluoromethyl)benzylidene) cyclohexanone, named C66, was a synthetic derivative of a naturally active curcumin(Pan et al., 2013). In our previous studies, C66 could inhibit the expression of inflammatory cytokines in high glucose- and lipopolysaccharide-stimulated mouse macrophages via exerting anti-inflammatory effects (Pan et al., 2014). C66 treatment significantly ameliorated cardiac inflammation, apoptosis, and dysfunction associated with diabetic cardiomyopathy (Pan et al., 2014; Wang et al., 2014). The protective effect of C66 in diabetic cardiomyopathy was mediated by direct inhibition of JNK-mediated inflammation and apoptosis (Pan et al., 2012; Wang et al., 2014). However, it was unknown whether C66 could improve myocardial infarction by targeting JNK-mediated inflammation and cellular apoptosis.

To this end, the present study aimed to investigate the pharmacological effects of C66 in mice after AMI, and to identify the responsible role of JNK signaling in cardiac inflammation and apoptosis. The present study will support the potential application of C66 in combating AMI dependent on JNK activation.