Abstract
NADPH oxidases derived reactive oxygen species (ROS) play an important role in vascular function and remodeling in hypertension through redox signaling processes. Previous studies demonstrated that protein disulfide isomerase (PDI) regulates Nox1 expression and ROS generation in cultured vascular smooth muscle cells. However, the role of PDI in conductance and resistance arteries during hypertension development remains unknown. The aim of the present study was to investigate PDI expression and NADPH oxidase dependent ROS generation during hypertension development. Mesenteric resistance arteries (MRA) and thoracic aorta were isolated from 6, 8, and 12 week-old spontaneously hypertensive (SHR) and Wistar rats. ROS production (dihydroethidium fluorescence), PDI (WB, imunofluorescence), Nox1 and NOX4 (RT-PCR) expression were evaluated. Results show a progressive increase in ROS generation in MRA and aorta from 8 to 12 week-old SHR. This effect was associated with a concomitant increase in PDI and Nox1 expression only in MRA. Therefore, suggesting a positive correlation between PDI and Nox1 expression during the development of hypertension in MRA. In order to investigate if this effect was due to an increase in arterial blood pressure, pre hypertensive SHR were treated with losartan (20 mg/kg/day for 30 days), an AT1 receptor antagonist. Losartan decreased blood pressure and ROS generation in both vascular beds. However, only in SHR MRA losartan treatment lowered PDI and Nox1 expression to control levels. In MRA PDI inhibition (bacitracin, 0.5 mM) decreased Ang II redox signaling (p-ERK 1/2). Altogether, our results suggest that PDI plays a role in triggering oxidative stress and vascular dysfunction in resistance but not in conductance arteries, increasing Nox1 expression and activity. Therefore, PDI could be a new player in oxidative stress and functional alterations in resistance arteries during the establishment of hypertension.
Highlights
Among the factors involved in the pathophysiology of hypertension evidence indicates an important role of reactive oxygen species (ROS) (Pechanova et al, 2006)
Hypertension Development is Accompanied by Oxidative Stress and Increased Nox-1/ protein disulfide isomerase (PDI) Expression Only in Mesenteric Resistance Arteries Figure 1 shows that spontaneously hypertensive (SHR) were normotensive at 6 weeks of age; at 8 weeks of age SHR presented an increase in blood pressure as compared to Wistar rats, which was even higher at 12 weeks and this stage was considered a phase of established hypertension
Involvement of PDI in hypertension vascular dysfunction associated with increased NADPH oxidase activity has not been investigated
Summary
Among the factors involved in the pathophysiology of hypertension evidence indicates an important role of reactive oxygen species (ROS) (Pechanova et al, 2006). An important source of ROS in the cardiovascular system is the NADPH oxidase family of enzymes These enzymes generate superoxide, that can reduce the bioavailability of nitric oxide (NO) as well as serve as a precursor for other species such as H2O2 and ONOO− (Rey et al, 2001). All Nox isoforms are transmembrane proteins capable of generating ROS, they differ in distribution and cellular localization, association with regulatory subunits, ROS generated and activation mechanisms. These differences are responsible for the different functions of Nox and confer specificity to the action of ROS as second messengers, making the generation of these species a controlled and compartmentalized event. NADPH oxidase activity can be regulated through assembly of the regulatory subunits to the membrane or by increased expression of the enzyme (Brandes and Schroder, 2008)
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