Abstract
BackgroundCaffeic acid phenethyl ester (CAPE) has been shown to protect the heart against ischemia/reperfusion (I/R) injury by various mechanisms including its antioxidant effect. In this study, we evaluated the protective effects of a CAPE analog with more structural stability in plasma, caffeic acid phenethyl amide (CAPA), on I/R injury in streptozotocin (STZ)-induced type 1 diabetic rats.MethodsType 1 diabetes mellitus was induced in Sprague–Dawley rats by a single intravenous injection of 60 mg/kg STZ. To produce the I/R injury, the left anterior descending coronary artery was occluded for 45 minutes, followed by 2 hours of reperfusion. CAPA was pretreated intraperitoneally 30 minutes before reperfusion. An analog devoid of the antioxidant property of CAPA, dimethoxyl CAPA (dmCAPA), and a nitric oxide synthase (NOS) inhibitor (Nω-nitro-l-arginine methyl ester [l-NAME]) were used to evaluate the mechanism involved in the reduction of the infarct size following CAPA-treatment. Finally, the cardioprotective effect of chronic treatment of CAPA was analyzed in diabetic rats.ResultsCompared to the control group, CAPA administration (3 and 15 mg/kg) significantly reduced the myocardial infarct size after I/R, while dmCAPA (15 mg/kg) had no cardioprotective effect. Interestingly, pretreatment with a NOS inhibitor, (l-NAME, 3 mg/kg) eliminated the effect of CAPA on myocardial infarction. Additionally, a 4-week CAPA treatment (1 mg/kg, orally, once daily) started 4 weeks after STZ-induction could effectively decrease the infarct size and ameliorate the cardiac dysfunction by pressure-volume loop analysis in STZ-induced diabetic animals.ConclusionsCAPA, which is structurally similar to CAPE, exerts cardioprotective activity in I/R injury through its antioxidant property and by preserving nitric oxide levels. On the other hand, chronic CAPA treatment could also ameliorate cardiac dysfunction in diabetic animals.
Highlights
Caffeic acid phenethyl ester (CAPE) has been shown to protect the heart against ischemia/reperfusion (I/R) injury by various mechanisms including its antioxidant effect
caffeic acid phenethyl amide (CAPA) protected the heart from I/R injury via a nitric oxide (NO)-dependent pathway To investigate the cardioprotective effects of CAPA against I/R injury in vivo, rats were intraperitoneally treated with CAPA (3 and 15 mg/kg) or dimethoxyl CAPA (dmCAPA) (CAPA derivative, methylation at the hydroxyl groups, no antioxidant activity; 15 mg/kg; Figure 1) 30 min before the reperfusion
(% of Area at risk (AAR)) in control rats treated with vehicle and in rats treated with CAPA (3 or 15 mg/kg) and dmCAPA (15 mg/kg). **P < 0.01 and ***P < 0.001 compared to vehicle. (C) AAR (% of ventricle) and (D) infarct size (% of AAR) in control rats treated with vehicle and in rats pretreated with Nω-nitro-L-arginine methyl ester (L-NAME) (3 mg/kg) and treated with CAPA (15 mg/kg). ###P < 0.001 compared to vehicle
Summary
Caffeic acid phenethyl ester (CAPE) has been shown to protect the heart against ischemia/reperfusion (I/R) injury by various mechanisms including its antioxidant effect. We evaluated the protective effects of a CAPE analog with more structural stability in plasma, caffeic acid phenethyl amide (CAPA), on I/R injury in streptozotocin (STZ)-induced type 1 diabetic rats. The infarct size of the heart is increased in streptozotocin (STZ)-induced type 1 diabetic rats under ischemia/reperfusion (I/R) injury [2,3]. CAPE can protect against I/R injury by various mechanisms [19,20,21,22,23] including its antioxidant activity
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