Abstract
H2 O2 contributes to FID of human arterioles. This study is designed to examine the roles of mitochondria and NADPH oxidase in modulating the release of ROS and in mediating FID. We tested whether NADPH oxidase contributes to mitochondrial ROS generation in arterioles during CAD. Visceral adipose arterioles obtained from patients with or without CAD were cannulated and pressurized for videomicroscopic measurement of arteriolar diameters. Dilator responses and ROS production during flow were determined in the presence and absence of the NADPH oxidase inhibitor gp91ds-tat and the mitochondrial electron transport inhibitor rotenone. Both dilation and H2 O2 generation during flow were reduced in the presence of rotenone (13.5±8% vs 97±% without rotenone) or gp91ds-tat in patients with CAD, while patients without CAD exhibited H2 O2 -independent dilations. Mitochondrial superoxide production during flow was attenuated by gp91ds-tat in arterioles from CAD patients. These findings indicate that ROS produced by NADPH oxidase are an upstream component of the mitochondria-dependent pathway contributing to flow-dependent H2 O2 generation and dilation in peripheral microvessels from patients with CAD. We conclude that in CAD, both mitochondria and NADPH oxidase contribute to FID through a redox mechanism in visceral arterioles.
Highlights
Vasodilation to an increase in blood flow is an important physiologic stimulus for regulating peripheral vascular tone and homeostasis
These findings indicate that reactive oxygen species (ROS) produced by NADPH oxidase are an upstream component of the mitochondria-dependent pathway contributing to flow-dependent H2O2 generation and dilation in peripheral microvessels from patients with coronary artery disease (CAD)
In pressurized arterioles isolated from visceral adipose of subjects undergoing thoracic or abdominal surgery, rotenone decreased dilations to flow in subjects with CAD (maximum dilation (MD): 72.5 ± 10.6% no rotenone vs. 32.6 ± 9.9% rotenone, P < 0.05; Figure 1A) but had no effect in subjects without CAD (Figure 1B) implicating a specific role for mitochondrial complex I in patients afflicted with CAD
Summary
Vasodilation to an increase in blood flow is an important physiologic stimulus for regulating peripheral vascular tone and homeostasis. Previous data shows a complex role for reactive oxygen species (ROS) in regulating vascular tone in cardiovascular disease. On one hand cardiovascular disease is associated with reduced flow-induced NO release due to the increased levels of superoxide. We and others have shown that an increase in the ROS hydrogen peroxide (H2O2), is responsible for endothelium- dependent vasodilation in animals [4] and in coronary [5] and visceral [6] arterioles from patients with coronary artery disease (CAD). Since human adipose is a source of paracrine modulation of vasomotion and vascular inflammation [8], alterations in the mechanisms mediating FID in arterioles embedded in adipose tissue may closely reflect this pro-inflammatory environment and may contribute to the development of cardiovascular disease
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