Abstract
Myocardial infarction is associated with oxidative stress and mitochondrial damage. However, the regulatory mechanisms underlying cardiomyocyte oxidative stress during myocardial infarction are not fully understood. In the present study, we explored the cardioprotective action of optic atrophy 1- (Opa1-) mediated mitochondrial autophagy (mitophagy) in oxidative stress-challenged cardiomyocytes, with a focus on mitochondrial homeostasis and the MAPK/ERK pathway. Our results demonstrated that overexpression of Opa1 in cultured rat H9C2 cardiomyocytes, a procedure that stimulates mitophagy, attenuates oxidative stress and increases cellular antioxidant capacity. Activation of Opa1-mediated mitophagy suppressed cardiomyocyte apoptosis by downregulating Bax, caspase-9, and caspase-12 and upregulating Bcl-2 and c-IAP. Using mitochondrial tracker staining and a reactive oxygen species indicator, our assays showed that Opa1-mediated mitophagy attenuated mitochondrial fission and reduced ROS production in cardiomyocytes. In addition, we found that inhibition of the MAPK/ERK pathway abolished the antioxidant action of Opa1-mediated mitophagy in these cells. Taken together, our data demonstrate that Opa1-mediated mitophagy protects cardiomyocytes against oxidative stress damage through inhibition of mitochondrial fission and activation of MAPK/ERK signaling. These findings reveal a critical role for Opa1 in the modulation of cardiomyocyte redox balance and suggest a potential target for the treatment of myocardial infarction.
Highlights
Oxidative stress in cardiomyocytes has been regarded as the primary pathological factor in many cardiovascular disorders including, but not limited to, diabetic cardiomyopathy, heart failure, myocardial hypertrophy, cardiac fibrosis, and dilated cardiomyopathy [1,2,3]
To investigate the role of optic atrophy 1- (Opa1-)related mitophagy on reactive oxygen species (ROS) production and mitochondrial dysfunction, cultured H9C2 cardiomyocytes were transduced with an adenoviral vector encoding optic atrophy 1 (Opa1) (Ad-Opa1)
Since mitochondrial ROS overproduction is associated with oxidative stress and mitochondrial and cellular dysfunction, we evaluated the functionality of mitochondria in both control and Opa1transduced cardiomyocytes
Summary
Oxidative stress in cardiomyocytes has been regarded as the primary pathological factor in many cardiovascular disorders including, but not limited to, diabetic cardiomyopathy, heart failure, myocardial hypertrophy, cardiac fibrosis, and dilated cardiomyopathy [1,2,3]. Oxidative stress induces the peroxidation of cellular membranes, including the mitochondrial membrane, the endoplasmic reticulum membrane, and the plasma membrane. Several antioxidative therapies have been developed to promote the recovery of cardiomyocyte function in cardiovascular disease, several questions remain regarding the upstream regulatory mechanisms controlling antioxidant responses in these cells [8,9,10,11]. Oxidative stress is primarily caused by excessive production and intracellular accumulation of reactive oxygen species (ROS) [12]. Whereas physiological (low) ROS levels serve signaling functions and contribute to adaptive responses to hypoxia, excess ROS overwhelms the cells’ antioxidant defenses and exacerbates mitochondrial ROS production to promote cell death [17]. Strategies aiming at protecting mitochondria and attenuating ROS production have great therapeutic potential in the management of cardiovascular
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