Abstract
Many studies have shown that crosstalk exists between apoptosis and autophagy, despite differences in mechanisms between these processes. Paeonol, a major phenolic compound isolated from Moutan Cortex Radicis, the root bark of Paeonia × suffruticosa Andrews (Paeoniaceae), is widely used in traditional Chinese medicine as an antipyretic, analgesic and anti-inflammatory agent. In this study, we investigated the detailed molecular mechanisms of the crosstalk between apoptosis and autophagy underlying the cardioprotective effects of paeonol in rats subjected to myocardial ischemia/reperfusion (I/R) injury. Myocardial I/R injury was induced by occlusion of the left anterior descending coronary artery (LAD) for 1 h followed by 3 h of reperfusion. Paeonol was intravenously administered 15 min before LAD ligation. We found that paeonol significantly improved cardiac function after myocardial I/R injury and significantly decreased myocardial I/R-induced arrhythmia and mortality. Paeonol also significantly decreased myocardial infarction and plasma LDH activity and Troponin-I levels in carotid blood after I/R. Compared with vehicle treatment, paeonol significantly upregulated Bcl-2 protein expression and significantly downregulated the cleaved forms of caspase-8, caspase-9, caspase-3 and PARP protein expression in the I/R injured myocardium. Myocardial I/R-induced autophagy, including the increase of Beclin-1, p62, LC3-I, and LC3-II protein expression in the myocardium was significantly reversed by paeonol treatment. Paeonol also significantly increased the Bcl-2/Bax and Bcl-2/Beclin-1 ratios in the myocardium after I/R injury. The cardioprotective role of paeonol during I/R injury may be due to its mediation of crosstalk between apoptotic and autophagic signaling pathways, which inhibits apoptosis and autophagic cell death.
Highlights
Recent studies have shown that cardiomyocyte death is the main reason for the poor prognosis of patients with ischemic heart disease (Chiong et al, 2011; Teringova and Tousek, 2017)
The effects of paeonol on arrhythmias and mortality elicited by myocardial I/R injury in anesthetzed rats are shown in Supplementary Table S1
We found that paeonol significantly increased the ratio of B-cell lymphoma-2 (Bcl-2) to Beclin-1 protein expression, but without changing the ratio of cleaved-caspase 8 and cleaved-caspase 3 to Beclin-1 protein expression after myocardial I/R injury compared with the control group (Figure 5)
Summary
Recent studies have shown that cardiomyocyte death is the main reason for the poor prognosis of patients with ischemic heart disease (Chiong et al, 2011; Teringova and Tousek, 2017). The most appropriate clinical strategy to limit myocardial infarct size, preserve cardiac function and improve both quality of life and survival in patients with ischemic heart disease is to minimize myocardial ischemia/reperfusion (I/R) injuryinduced cardiomyocyte death, such as necrosis, apoptosis, or autophagy (Tian et al, 2013). Apoptosis and autophagy differ from necrosis, in that neither apoptosis nor autophagy exhibit myocardial inflammation and they share many death signals that regulate cell death, which may be important signaling pathways in myocardial I/R injury (Oerlemans et al, 2013). After interacting with Bcl-2, Beclin-1 is sequestrated away from the Vps34/class III PI3K complex and autophagy is inhibited, whereas Bcl-2 maintains anti-apoptotic potential (Levine et al, 2008; Ciechomska et al, 2009). Evidence has shown that the interplay between autophagy and apoptosis is closely related to I/R injury, so recent studies have focused on the crosstalk between these cell death processes (Li M. et al, 2016; Dong et al, 2019)
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