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Effects of angiotensin II on the cerebral circulation: role of oxidative stress.

De Silva TM, Faraci FM - Front Physiol (2013)

Bottom Line: Angiotensin II (Ang II) is the main effector peptide of the renin-angiotensin system (RAS) and plays a critical role in promoting oxidative stress in the vasculature.Importantly, many of the aforementioned effects have been shown to be dependent on NADPH oxidases.This review will focus on our current understanding of the contribution of Ang II and NADPH oxidases to oxidative stress in the cerebral circulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Cardiovascular Center, The University of Iowa Carver College of Medicine Iowa City, IA, USA.

ABSTRACT
Oxidative stress has emerged as a key component of many diseases that affect the vasculature. Oxidative stress is characterized as a cellular environment where the generation of oxidant molecules overwhelms endogenous anti-oxidant defense mechanisms. NADPH oxidases are a family of enzymes whose primary purpose is generation of reactive oxygen species (oxidant molecules) and therefore are likely to be key contributors to oxidative stress. Hypertension is associated with oxidative stress in the vasculature and is a major risk factor for stroke and cognitive abnormalities. Angiotensin II (Ang II) is the main effector peptide of the renin-angiotensin system (RAS) and plays a critical role in promoting oxidative stress in the vasculature. In the cerebral circulation, Ang II has been implicated in reactive oxygen species generation, alterations to vasomotor function, impaired neurovascular coupling, inflammation, and vascular remodeling. Furthermore, studies in humans have shown that cerebral blood flow is altered during hypertension and therapeutically targeting the RAS improves cerebral blood flow. Importantly, many of the aforementioned effects have been shown to be dependent on NADPH oxidases. Thus, Ang II, NADPH oxidases and oxidative stress are likely to play key roles in the pathogenesis of hypertension and associated cerebrovascular disease. This review will focus on our current understanding of the contribution of Ang II and NADPH oxidases to oxidative stress in the cerebral circulation.

No MeSH data available.


Related in: MedlinePlus

Interactions between nitric oxide (NO·) and reactive oxygen species (ROS). NO· is a critical component of mechanisms that regulate cerebrovascular homeostasis. Diverse stimuli (including shear stress, neurotransmitters like acetylcholine and activation of neurons) can result in the generation of NO· by either endothelial or neuronal nitric oxide synthase (eNOS and nNOS, respectively). The generation of NO· is dependent on the presence of the substrate L-arginine (L-Arg) and enzyme co-factors including tetrahydrobiopterin (BH4). NO· activates its receptor in vascular muscle soluble guanylate cyclase (sGC), which results in the formation of cyclic guanosine monophosphate (cGMP). This results in numerous signaling events and functional effects which include cerebral vasodilation. NADPH oxidases (Nox1 and Nox2) generate superoxide (O2·−) and Nox4 can generate hydrogen peroxide (H2O2), ROS can then participate in signaling events, but may also cause cellular injury. O2·− is a potent scavenger of NO·, which reduces the bioavailability of NO· and results in the formation of peroxynitrite (ONOO−), which also causes cellular injury. H2O2 can react with heavy metals to form the highly reactive and toxic hydroxyl radical (OH·).
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Figure 1: Interactions between nitric oxide (NO·) and reactive oxygen species (ROS). NO· is a critical component of mechanisms that regulate cerebrovascular homeostasis. Diverse stimuli (including shear stress, neurotransmitters like acetylcholine and activation of neurons) can result in the generation of NO· by either endothelial or neuronal nitric oxide synthase (eNOS and nNOS, respectively). The generation of NO· is dependent on the presence of the substrate L-arginine (L-Arg) and enzyme co-factors including tetrahydrobiopterin (BH4). NO· activates its receptor in vascular muscle soluble guanylate cyclase (sGC), which results in the formation of cyclic guanosine monophosphate (cGMP). This results in numerous signaling events and functional effects which include cerebral vasodilation. NADPH oxidases (Nox1 and Nox2) generate superoxide (O2·−) and Nox4 can generate hydrogen peroxide (H2O2), ROS can then participate in signaling events, but may also cause cellular injury. O2·− is a potent scavenger of NO·, which reduces the bioavailability of NO· and results in the formation of peroxynitrite (ONOO−), which also causes cellular injury. H2O2 can react with heavy metals to form the highly reactive and toxic hydroxyl radical (OH·).

Mentions: Oxidative stress is characterized by a shift from a cellular environment where the production and metabolism of oxidant molecules are tightly controlled to one of elevated levels of the same molecules. The excess oxidant molecules may then overwhelm anti-oxidant defense systems, resulting in oxidative stress. Such a shift in balance can occur due to an overproduction of ROS, such as superoxide (O2·−), or a reduction in the removal of ROS by oxidant defense mechanisms. Key anti-oxidants include O2·− dismutases (SOD), glutathione peroxidases, and catalase. ROS can be generated by multiple enzymes within the vasculature as well as non-enzymatic sources. O2·− anion is the parent ROS molecule produced by the one electron reduction of molecular oxygen by various oxidases (e.g., NADPH oxidase, cyclooxygenase, enzymes in the mitochondrial electron transport chain, lipoxygenases, cytochrome P450 enzymes). O2·− can then be dismutated by SOD, resulting in the generation of hydrogen peroxide (H2O2; Figure 1). These ROS can undergo further enzymatic or non-enzymatic reactions to generate other powerful oxidant molecules, such as hydroxyl radical (OH·), peroxynitrite (ONOO−), and hyperchlorous acid (HOCl) (Chrissobolis and Faraci, 2008; Miller et al., 2010) (Figure 1).


Effects of angiotensin II on the cerebral circulation: role of oxidative stress.

De Silva TM, Faraci FM - Front Physiol (2013)

Interactions between nitric oxide (NO·) and reactive oxygen species (ROS). NO· is a critical component of mechanisms that regulate cerebrovascular homeostasis. Diverse stimuli (including shear stress, neurotransmitters like acetylcholine and activation of neurons) can result in the generation of NO· by either endothelial or neuronal nitric oxide synthase (eNOS and nNOS, respectively). The generation of NO· is dependent on the presence of the substrate L-arginine (L-Arg) and enzyme co-factors including tetrahydrobiopterin (BH4). NO· activates its receptor in vascular muscle soluble guanylate cyclase (sGC), which results in the formation of cyclic guanosine monophosphate (cGMP). This results in numerous signaling events and functional effects which include cerebral vasodilation. NADPH oxidases (Nox1 and Nox2) generate superoxide (O2·−) and Nox4 can generate hydrogen peroxide (H2O2), ROS can then participate in signaling events, but may also cause cellular injury. O2·− is a potent scavenger of NO·, which reduces the bioavailability of NO· and results in the formation of peroxynitrite (ONOO−), which also causes cellular injury. H2O2 can react with heavy metals to form the highly reactive and toxic hydroxyl radical (OH·).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3539653&req=5

Figure 1: Interactions between nitric oxide (NO·) and reactive oxygen species (ROS). NO· is a critical component of mechanisms that regulate cerebrovascular homeostasis. Diverse stimuli (including shear stress, neurotransmitters like acetylcholine and activation of neurons) can result in the generation of NO· by either endothelial or neuronal nitric oxide synthase (eNOS and nNOS, respectively). The generation of NO· is dependent on the presence of the substrate L-arginine (L-Arg) and enzyme co-factors including tetrahydrobiopterin (BH4). NO· activates its receptor in vascular muscle soluble guanylate cyclase (sGC), which results in the formation of cyclic guanosine monophosphate (cGMP). This results in numerous signaling events and functional effects which include cerebral vasodilation. NADPH oxidases (Nox1 and Nox2) generate superoxide (O2·−) and Nox4 can generate hydrogen peroxide (H2O2), ROS can then participate in signaling events, but may also cause cellular injury. O2·− is a potent scavenger of NO·, which reduces the bioavailability of NO· and results in the formation of peroxynitrite (ONOO−), which also causes cellular injury. H2O2 can react with heavy metals to form the highly reactive and toxic hydroxyl radical (OH·).
Mentions: Oxidative stress is characterized by a shift from a cellular environment where the production and metabolism of oxidant molecules are tightly controlled to one of elevated levels of the same molecules. The excess oxidant molecules may then overwhelm anti-oxidant defense systems, resulting in oxidative stress. Such a shift in balance can occur due to an overproduction of ROS, such as superoxide (O2·−), or a reduction in the removal of ROS by oxidant defense mechanisms. Key anti-oxidants include O2·− dismutases (SOD), glutathione peroxidases, and catalase. ROS can be generated by multiple enzymes within the vasculature as well as non-enzymatic sources. O2·− anion is the parent ROS molecule produced by the one electron reduction of molecular oxygen by various oxidases (e.g., NADPH oxidase, cyclooxygenase, enzymes in the mitochondrial electron transport chain, lipoxygenases, cytochrome P450 enzymes). O2·− can then be dismutated by SOD, resulting in the generation of hydrogen peroxide (H2O2; Figure 1). These ROS can undergo further enzymatic or non-enzymatic reactions to generate other powerful oxidant molecules, such as hydroxyl radical (OH·), peroxynitrite (ONOO−), and hyperchlorous acid (HOCl) (Chrissobolis and Faraci, 2008; Miller et al., 2010) (Figure 1).

Bottom Line: Angiotensin II (Ang II) is the main effector peptide of the renin-angiotensin system (RAS) and plays a critical role in promoting oxidative stress in the vasculature.Importantly, many of the aforementioned effects have been shown to be dependent on NADPH oxidases.This review will focus on our current understanding of the contribution of Ang II and NADPH oxidases to oxidative stress in the cerebral circulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Cardiovascular Center, The University of Iowa Carver College of Medicine Iowa City, IA, USA.

ABSTRACT
Oxidative stress has emerged as a key component of many diseases that affect the vasculature. Oxidative stress is characterized as a cellular environment where the generation of oxidant molecules overwhelms endogenous anti-oxidant defense mechanisms. NADPH oxidases are a family of enzymes whose primary purpose is generation of reactive oxygen species (oxidant molecules) and therefore are likely to be key contributors to oxidative stress. Hypertension is associated with oxidative stress in the vasculature and is a major risk factor for stroke and cognitive abnormalities. Angiotensin II (Ang II) is the main effector peptide of the renin-angiotensin system (RAS) and plays a critical role in promoting oxidative stress in the vasculature. In the cerebral circulation, Ang II has been implicated in reactive oxygen species generation, alterations to vasomotor function, impaired neurovascular coupling, inflammation, and vascular remodeling. Furthermore, studies in humans have shown that cerebral blood flow is altered during hypertension and therapeutically targeting the RAS improves cerebral blood flow. Importantly, many of the aforementioned effects have been shown to be dependent on NADPH oxidases. Thus, Ang II, NADPH oxidases and oxidative stress are likely to play key roles in the pathogenesis of hypertension and associated cerebrovascular disease. This review will focus on our current understanding of the contribution of Ang II and NADPH oxidases to oxidative stress in the cerebral circulation.

No MeSH data available.


Related in: MedlinePlus