Cinnamic acid preserves against myocardial ischemia/reperfusion injury via suppression of NLRP3/Caspase-1/GSDMD signaling pathway

Background: Cinnamic acid (CA) is an active organic acid compound extracted from Cinnamomi ramulus that has various biological activities. There is growing studies have shown that the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome significantly contributes to sterile inflammatory response and pyroptosis in myocardial ischemia/reperfusion injury (MI/RI). However, whether CA has any influence on NLRP3 inflammasome and pyroptosis during MI/RI are not fully elucidated. Purpose: In the present study, we investigated whether NLRP3 inflammasome activation and pyroptosis were involved in the cardioprotective effect of CA against MI/RI. Methods: Male Sprague-Dawley rats were intragastrically administered either with CA (75 and 150 mg/kg, daily) or vehicle for 7 successive days prior to ligation of coronary artery, and then rats were subjected to ligation of the left anterior descending coronary artery for 30 min followed by reperfusion for 120 min to evoke MI/RI. Results: Our results demonstrated that CA could significantly improve cardiac diastolic function, decrease cardiac infarct size and myocardial injury enzymes, inhibit cardiomyocyte apoptosis, attenuate cardiac structure abnormality, and mitigate oxidative stress and inflammatory response. We also found that MI/RI activate NLRP3 inflammasome as evidenced by the upregulation levels of NLRP3, pro-caspase-1, caspase-1, and ASC proteins and mRNA. More importantly, MI/RI trigger pyroptosis as indicated by increased DNA fragmentation, membrane pore formation, and mitochondrial swelling as well as increased levels of pyroptosis-related proteins and mRNA, including GSDMD, N-GSDMD, IL-18, and IL-1 beta. As expected, all these deleterious alterations were prominently reversed by CA pretreatment. Conclusions: These findings indicate that CA effectively protected cardiomyocytes against MI/RI by inhibiting NLRP3/Caspase-1/GSDMD signaling pathway, and it is worthy of more investigations for its therapeutic potential for extenuating ischemic heart disease.