An appraisal of the role of asymmetric dimethylarginine on endothelial impairment in preeclampsia comorbid with HIV infection.

Asymmetric dimethylarginine (ADMA) is an endogenous eNOS competitive inhibitor that plays a critical role in regulating the bioavailability and homeostasis of nitric oxide (NO) and vascularity. The conditions of both preeclampsia (PE) and HIV infection have their endothelial impairment as their basis, and their prevalence is very high in sub-Saharan Africa, as well as their frequent comorbidity during pregnancy. Elevated ADMA amount suppresses the NO synthesis, which stimulates vasoconstriction, oxidative stress, and inflammation in the vascular wall, which are pathogenic events in PE and cardiovascular risk in HIV. While ADMA has been examined in PE and HIV research separately, its role in women presenting with both conditions during pregnancy is not well understood. Therefore, we conducted a critical review to determine whether ADMA acts as a mechanistic bridge between the involvement of HIV-mediated immune activation, oxidative stress, and the antiretroviral therapy (ART)-induced vascular perturbations, and the endothelial dysfunction that is typical of PE. We evaluated the PRMT-DDAH1-ADMA eNOS axis, outlining the growing evidence that DDAH1 and DDAH2 are the main metabolic enzymes of ADMA, and that ADMA activity is extremely vulnerable to oxidative inactivation. We compared evidence, based on PE-only, HIV-only, and HIV+PE cohorts, and combined the current primary clinical research, which revealed high ADMA levels, poor L-arginine/ADMA ratios, and DDAH gene polymorphism in HIV-associated PE in women. These findings suggest that inflammatory signaling and reactive oxygen species are associated with HIV infection and can potentially inhibit the activity of DDAH1 and increase PRMT-mediated methylation, contributing to systematic accumulation of ADMA and a deficiency of NO during pregnancy. We also investigated how the proteins of HIV infection (gp120, Tat, and Nef) mediate the increase in endothelial activity and oxidative stress, and explained how these proteins may have an indirect effect on the regulation of ADMA via inflammatory and redox-sensitive pathways. Even though the initiation of ART has been observed to be correlated with the decrease in circulating levels of ADMA in non-pregnancy HIV cohorts, it is not clear what the clinical effect of this decrease in pregnancy is, namely, immune reconstitution, angiogenic imbalance, and PE susceptibility. Thus, filling in mechanistic, genetic, and clinical evidence, our study determines the gaps in learning about the ADMA-HIV-PE axis and measures whether the modulation of the L-arginine/ADMA ratio or DDAH1 activity is a plausible diagnostic or treatment option. We present that an understanding of this pathway is key to the development of biomarkers and in the development of focused, situation-specific interventions, where resources are scarce, and the burden of disease is increasing.