Abstract
Age-associated decline in cardiovascular function is believed to occur from the deleterious effects of reactive oxygen species (ROS). However, failure of recent clinical trials using antioxidants in patients with cardiovascular disease, and the recent findings showing paradoxical role for NADPH oxidase-derived ROS in endothelial function challenge this long-held notion against ROS. Here, we examine the effects of endothelium-specific conditional increase in ROS on coronary endothelial function. We have generated a novel binary (Tet-ON/OFF) conditional transgenic mouse (Tet-Nox2:VE-Cad-tTA) that induces endothelial cell (EC)-specific overexpression of Nox2/gp91 (NADPH oxidase) and 1.8?0.42-fold increase in EC-ROS upon tetracycline withdrawal (Tet-OFF). We examined ROS effects on EC signaling and function. First, we demonstrate that endothelium-dependent coronary vasodilation was significantly improved in Tet-OFF Nox2 compared to Tet-ON (control) littermates. Using EC isolated from mouse heart, we show that endogenous ROS increased eNOS activation and nitric oxide (NO) synthesis through activation of the survival kinase AMPK. Coronary vasodilation in Tet-OFF Nox2 animals was CaMKK?-AMPK-dependent. Finally, we demonstrate that AMPK activation induced autophagy and thus, protected ECs from oxidant-induced cell death. Together, these findings suggest that increased ROS levels, often associated with cardiovascular conditions in advanced age, play a protective role in endothelial homeostasis by inducing AMPK-eNOS axis.
Highlights
Increased levels of reactive oxygen species (ROS) are often associated with microvascular pathology in agerelated cardiovascular diseases (CVD) including coronary artery disease (CAD) and ischemic heart disease (IHD) - the major causes of death and morbidity in the USA[1,2,3]
Using isolated mouse heart endothelial cell (EC) (MHEC) and coronary microvessels, we demonstrate that conditional increase in EC-specific ROS induces AMPK-eNOS-mediated endothelium-dependent coronary vasodilatation, and AMPK-mTOR-mediated protective autophagy in MHEC
In order to examine the effects of Nox2 overexpression in ECs, mouse heart endothelial cells (MHEC) were isolated from two independent binary transgenic mouse lines as described [10]
Summary
Increased levels of reactive oxygen species (ROS) are often associated with microvascular pathology in agerelated cardiovascular diseases (CVD) including coronary artery disease (CAD) and ischemic heart disease (IHD) - the major causes of death and morbidity in the USA[1,2,3] These observations have led to the current paradigms in the field of cardiovascular and stroke research that reduction in ROS levels in the vessel walls should improve vascular functions [4]. Instead, reduced ROS levels resulted in the disruption of the signal transduction events that are essential for nitric oxide (NO) generation in vascular endothelium[10, 13,14,15], which in turn impaired vasodilatation[10, 14, 16] Together, these findings suggest that increased ROS levels often present in elderly patients with CVD may play critical roles in endothelial function
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