Role of Monocyte Oxidative Stress and Mineralocorticoid Receptor Signaling on Cardiovascular Disease and Persistent Inflammation in Antiretroviral-Treated HIV+ Persons

-
Investigator: Jeffrey Milush, PhD
Sponsor: NIH National Heart, Lung, and Blood Institute

Location(s): United States

Description

Combination antiretroviral therapy for HIV-1 infected persons has dramatically reduced AIDS-related causes of death, however these individuals are now facing new clinical issues including an increased risk of cardiovascular disease, which can impact quality of life and lifespan. While cortisol signaling through the glucocorticoid receptor has well described anti-inflammatory properties, emerging data from our lab suggests cortisol signaling through the mineralocorticoid receptor under oxidative stress may promote monocyte inflammatory activation and play a critical role in cardiovascular disease. This proposal aims to study the inflammatory role of monocyte mineralocorticoid receptor signaling to not only strengthen our understanding of cardiovascular disease in HIV-infected patients, but also more broadly serve as a model to advance our overall understanding of the immune system's role in cardiovascular disease.

Worldwide, heart disease remains the leading cause of death for more than a decade and a leading cause of death in the United States. Combination antiretroviral therapy (cART) has reduced HIV-related morbidity and mortality; however these patients are now facing new clinical issues including increased risk of cardiovascular disease (CVD). Among HIV+ individuals in the United States, CVD is the leading non-AIDS-related cause of death. Chronic inflammation and myeloid cell dysregulation are key features of both CVD and HIV infection, but how they are biologically linked remains poorly understood. We will use specimens from HIV+ participants in ongoing clinical studies of HIV and CVD as a model to understand the factors that may regulate monocyte responses that contribute to CVD. Nuclear hormone receptors play an important role in monocyte activation and differentiation. We will assess the role of two nuclear hormone receptors, the glucocorticoid and mineralocorticoid receptors, for their role in low-grade chronic inflammation and risk of CVD observed in cART- suppressed HIV+ patients. While the glucocorticoid receptor has well-defined anti-inflammatory functions in immune cells, the mineralocorticoid receptor has predominantly been studied in renal epithelial cells. In comparison, very little is known about mineralocorticoid receptor expression and function in human immune cells or its connection with physiologic and pathophysiologic conditions. The proposed studies take advantage of several innovative flow cytometry-based assays developed in our laboratory that allow simultaneous quantitative measures of the glucocorticoid and mineralocorticoid receptor expression and function with immune cell phenotype as well as a novel flow cytometry-based quantitative mRNA assay to measure gene transcripts on a per cell basis. We will use these assays to assess whether cortisol-induced activation of the mineralocorticoid receptor in monocytes results in pro-inflammatory/pro-fibrotic cytokine production and accelerated CVD in cART-suppressed HIV+ patients. We will use specimens from HIV+ participants in ongoing clinical studies of HIV and CVD to assess the relationships between oxidative stress, inflammation and corticosteroid receptor expression and signaling with carotid artery intima-media thickness measures. We will then explore the molecular pathways involved in mineralocorticoid receptor signaling during oxidative stress using specific inhibitors of oxidases, redox-sensitive serine kinases and corticosteroid receptor antagonists. This project is expected to provide novel insights into an unexplored area of corticosteroid receptor signaling in monocytes that will not only strengthen our understanding of this mechanism in CVD pathogenesis, but will also enable the development of additional mechanistic studies to characterize this important signaling pathway in immune cells. The availability of mineralocorticoid receptor antagonists, as well as the ongoing development of oxidase and kinase inhibitors, further enhance the potential clinical impact of this research, as there are clear potential pathways for translating insights from this bench research to the bedside.