TY - JOUR
T1 - Role of reactive oxygen species in hyperadrenergic hypertension
T2 - Biochemical, physiological, and pharmacological evidence from targeted ablation of the chromogranin A (Chga) gene
AU - Gayen, Jiaur R.
AU - Zhang, Kuixing
AU - RamachandraRao, Satish P.
AU - Mahata, Manjula
AU - Chen, Yuqing
AU - Kim, Hyung Suk
AU - Naviaux, Robert K.
AU - Sharma, Kumar
AU - Mahata, Sushil K.
AU - O'Connor, Daniel T.
PY - 2010/10
Y1 - 2010/10
N2 - Background-Oxidative stress, an excessive production of reactive oxygen species (ROS) outstripping antioxidant defense mechanisms, occurs in cardiovascular pathologies, including hypertension. In the present study, we used biochemical, physiological, and pharmacological approaches to explore the role of derangements of catecholamines, ROS, and the endothelium-derived relaxing factor nitric oxide (NO') in the development of a hyperadrenergic model of hereditary hypertension: targeted ablation (knockout [KO]) of chromogranin A (Chga) in the mouse. Methods and Results-Homozygous (-/-) Chga gene knockout (KO) mice were compared with wild-type (WT, +/+) control mice. In the KO mouse, elevations of systolic and diastolic blood pressure were accompanied by not only elevated catecholamine (norepinephrine and epinephrine) concentrations but also increased ROS (H2O2) and isoprostane (an index of lipid peroxidation), as well as depletion of NO'. Renal transcript analyses implicated changes in Nox1/2, Xo/Xdh, and Sod1,2 mRNAs in ROS elevation by the KO state. KO alterations in blood pressure, catecholamines, H2O2, isoprostane, and NO' could be abrogated or even normalized (rescued) by either sympathetic outflow inhibition (with clonidine) or NADPH oxidase inhibition (with apocynin). In cultured renal podocytes, H2O2 production was substantially augmented by epinephrine (probably through β2-adrenergic receptors) and modestly diminished by norepinephrine (probably through α1 -adrenergic receptors). Conclusions-ROS appear to play a necessary role in the development of hyperadrenergic hypertension in this model, in a process mechanistically linking elevated blood pressure with catecholamine excess, renal transcriptional responses, ROS elevation, lipid peroxidation, and NO' depletion. Some of the changes appear to be dependent on transcription, whereas others are immediate. The cycle could be disrupted by inhibition of either sympathetic outflow or NADPH oxidase. Because common genetic variation at the human CHGA locus alters BP, the results have implications for antihypertensive treatment as well as prevention of target-organ consequences of the disease. The results document novel pathophysiological links between the adrenergic system and oxidative stress and suggest new strategies to probe the role and actions of ROS within this setting.
AB - Background-Oxidative stress, an excessive production of reactive oxygen species (ROS) outstripping antioxidant defense mechanisms, occurs in cardiovascular pathologies, including hypertension. In the present study, we used biochemical, physiological, and pharmacological approaches to explore the role of derangements of catecholamines, ROS, and the endothelium-derived relaxing factor nitric oxide (NO') in the development of a hyperadrenergic model of hereditary hypertension: targeted ablation (knockout [KO]) of chromogranin A (Chga) in the mouse. Methods and Results-Homozygous (-/-) Chga gene knockout (KO) mice were compared with wild-type (WT, +/+) control mice. In the KO mouse, elevations of systolic and diastolic blood pressure were accompanied by not only elevated catecholamine (norepinephrine and epinephrine) concentrations but also increased ROS (H2O2) and isoprostane (an index of lipid peroxidation), as well as depletion of NO'. Renal transcript analyses implicated changes in Nox1/2, Xo/Xdh, and Sod1,2 mRNAs in ROS elevation by the KO state. KO alterations in blood pressure, catecholamines, H2O2, isoprostane, and NO' could be abrogated or even normalized (rescued) by either sympathetic outflow inhibition (with clonidine) or NADPH oxidase inhibition (with apocynin). In cultured renal podocytes, H2O2 production was substantially augmented by epinephrine (probably through β2-adrenergic receptors) and modestly diminished by norepinephrine (probably through α1 -adrenergic receptors). Conclusions-ROS appear to play a necessary role in the development of hyperadrenergic hypertension in this model, in a process mechanistically linking elevated blood pressure with catecholamine excess, renal transcriptional responses, ROS elevation, lipid peroxidation, and NO' depletion. Some of the changes appear to be dependent on transcription, whereas others are immediate. The cycle could be disrupted by inhibition of either sympathetic outflow or NADPH oxidase. Because common genetic variation at the human CHGA locus alters BP, the results have implications for antihypertensive treatment as well as prevention of target-organ consequences of the disease. The results document novel pathophysiological links between the adrenergic system and oxidative stress and suggest new strategies to probe the role and actions of ROS within this setting.
KW - Chromogranin A
KW - Hypertension
KW - Nitric oxide
KW - Reactive oxygen species
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UR - http://www.scopus.com/inward/citedby.url?scp=78649364973&partnerID=8YFLogxK
U2 - 10.1161/CIRCGENETICS.109.924050
DO - 10.1161/CIRCGENETICS.109.924050
M3 - Article
C2 - 20729505
AN - SCOPUS:78649364973
SN - 1942-325X
VL - 3
SP - 414
EP - 425
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
IS - 5
ER -