Abstract
Endoplasmic reticulum (ER) stress induced apoptosis plays a pivotal role in myocardial ischemia/reperfusion (I/R)-injury. Inhibiting ER stress is a major therapeutic target/strategy in treating cardiovascular diseases. Our previous studies revealed that lycopene exhibits great pharmacological potential in protecting against the I/R-injury in vitro and vivo, but whether attenuation of ER stress (and) or ER stress-induced apoptosis contributes to the effects remains unclear. In the present study, using neonatal mouse cardiomyocytes to establish an in vitro model of hypoxia/reoxygenation (H/R) to mimic myocardium I/R in vivo, we aimed to explore the hypothesis that lycopene could alleviate the ER stress and ER stress-induced apoptosis in H/R-injury. We observed that lycopene alleviated the H/R injury as revealed by improving cell viability and reducing apoptosis, suppressed reactive oxygen species (ROS) generation and improved the phosphorylated AMPK expression, attenuated ER stress as evidenced by decreasing the expression of GRP78, ATF6 mRNA, sXbp-1 mRNA, eIF2α mRNA and eIF2α phosphorylation, alleviated ER stress-induced apoptosis as manifested by reducing CHOP/GADD153 expression, the ratio of Bax/Bcl-2, caspase-12 and caspase-3 activity in H/R-treated cardiomyocytes. Thapsigargin (TG) is a potent ER stress inducer and used to elicit ER stress of cardiomyocytes. Our results showed that lycopene was able to prevent TG-induced ER stress as reflected by attenuating the protein expression of GRP78 and CHOP/GADD153 compared to TG group, significantly improve TG-caused a loss of cell viability and decrease apoptosis in TG-treated cardiomyocytes. These results suggest that the protective effects of lycopene on H/R-injury are, at least in part, through alleviating ER stress and ER stress-induced apoptosis in neonatal mouse cardiomyocytes.
Highlights
Myocardial ischemia/reperfusion (I/R)-injury remains a major clinical problem in these patients that receive therapies including percutaneous coronary intervention, thrombolysis, coronary artery bypass grafting and cardiac transplantation [1, 2]
reactive oxygen species (ROS) generation is recognized as an early event in the process of myocardial I/R [9] and some studies have shown that cardiomyocytes H/R causes ROS generation [12, 41]
Increasing evidences have demonstrated that AMPK inactivation-mediated endoplasmic reticulum (ER) stress involved in and contributed to I/Rinjury, and activation of AMPK followed by inhibiting ER stress could reduce myocardial I/R or H/R injury [22,23,24]
Summary
Myocardial ischemia/reperfusion (I/R)-injury remains a major clinical problem in these patients that receive therapies including percutaneous coronary intervention, thrombolysis, coronary artery bypass grafting and cardiac transplantation [1, 2]. Conditions of myocardial reperfusion continue to improve with advances in perioperative cares and surgical techniques, there is still no effective therapy for preventing myocardial I/R-injury. Myocardial I/R-injury is a complicated pathological process, its underlying mechanisms span a broad range of fundamental biological changes, including ionic, inflammatory, oxidant stress, mitochondria dysfunction and apoptosis. These mechanisms have yet to be fully understood [3]. Recent studies have demonstrated that endoplasmic reticulum (ER) is closely associated with I/R-injury [4, 5]
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