Role of nitric oxide synthase 3 (NOS3) gene expression in patients of pre-eclampsia with special reference to cardiovascular and renal pathophysiology

Abstract

Background: Pre-eclampsia (PE) is a disorder that complicates pregnancy and is causing a rise in maternal and fetal morbidity and mortality. Oxidative stress affects patients of preeclampsia and is implicated in the pathogenesis. Gene expression of nitric oxide synthase (NOS) is altered and may contribute to cardiac and renal pathophysiology of pre-eclampsia. Aim: The aim of the study was to determine the relationship between the gene expression of nitric oxide synthase and oxidative/nitrosative stress, which thereby could influence the cardiovascular and renal pathophysiology in pre-eclampsia patients. Methods: Preeclampsia patients and normal pregnancy women were included in this case control study. Arterial blood pressure and heart rate were recorded. Frequency and time domain heart rate variability (HRV) analysis was done using the powerlab software. Levels of malondialdehyde (MDA), total antioxidant capacity and nitric oxide (NO) in the serum were estimated. Renal functions were determined by estimating serum proteins, urea, creatinine, uric acid and urine proteins and creatinine estimation. Urine angiotensinogen was also estimated. Urine protein/creatinine ratio and urine angiotensinogen/creatinine ratio were calculated later. Real-time polymerase chain reaction (RT-PCR) was used for nitric oxide synthase 3 (NOS3) and NOS2 gene profiling. Student’s t-test was used for statistical analysis and p value <0.05 was considered statistically significant. Results: A significantly higher (p<0.0001) mean arterial pressure was seen in the PE group. A significant increase was noted in LF/HF ratio, low frequency (LF) component, and a decrease in high frequency (HF) component of the HRV in pre-eclampsia. The time domain parameters, SDNN, SDANN, RMSSD and pNN50%, of HRV in preeclampsia patients, showed a reduction in their levels. Levels o f serum malondialdehyde were increased (p< 0.0001), and on the other hand, the total antioxidant capacity was decreased in the PE group (p= 0.034). A significant decrease in the serum albumin (p=0.004) and an increase in the serum uric acid (p<0.0001) were seen. Urine protein and urine protein: creatinine ratio were significantly higher (p<0.0001). The urinary excretion of angiotensinogen was significantly reduced (p<0.0001). But, the serum levels of NO did not show a statistically significant reduction (p = 0.20). Gene expression profiling in the PE group showed a down regulation of NOS3 and NOS2 by about 8.49 and 51.05 times respectively. Conclusion: Mean arterial pressure increase in preeclampsia may be due to endothelial dysfunction resulting from oxidative stress. Also, parasympathetic withdrawal along with sympathetic overactivity, noted in pre-eclampsia patients, may suggest cardiovascular risk in them, which may be detected early by HRV analysis. These changes may also trigger renal dysfunction. Nitric oxide could have played an important role as the mRNA expression of both NOS3 and NOS2 genes were reduced. However, cross-talk of NO with other vasoactive /biological substances cannot be overlooked