Alterations in Renin-Angiotensin System (RAS) Peptide Levels in Patients with HIV

Abstract

Chronic HIV infection has long been associated with an increased risk for cardiovascular diseases. The metabolites of the renin−angiotensin system (RAS) such as angiotensin II (AngII) play an important role in regulating blood pressure and fluid dynamics. Cross-sectional analysis of HIV-positive individuals (n = 71, age > 40 years, stable ART > 3 months with HIV viral load < 50 copies/mL) were compared to a similar HIV seronegative group (n = 72). High-resolution B-mode ultrasound images of the right carotid bifurcation (RBIF) and right common carotid artery (RCCA) were conducted to measure the extent of carotid atherosclerotic vascular disease. Plasma RAS peptide levels were quantified using a liquid chromatography-mass spectrometry-based metabolomics assay. RAS peptide concentrations were compared between persons with HIV and persons without HIV, correlating their association with clinical and cardiac measures. Median precursor peptides (Ang(1-12) and AngI) were significantly higher in the HIV-positive group compared to the HIV-negative. Analyses of the patient subgroup not on antihypertensive medication revealed circulating levels of AngII to be four-fold higher in the HIV-positive subgroup. AngII and TNF-alpha levels were found to have a positive association with RCCA, and AngI/Ang(1-12) ratio and TNF-alpha levels were found to have a positive association with RBIF. In both predictive models, AngIII had a negative association with either RCCA or RBIF, which may be attributed to its ability to bind onto AT2R and thus oppose pro-inflammatory events. These results reveal systemic alterations in RAS as a result of chronic HIV infection, which may lead to the activation of inflammatory pathways associated with carotid thickening. RAS peptide levels and cytokine markers were associated with RCCA and RBIF measurements.

Keywords: HIV; carotid thickening; metabolomics; renin-angiotensin system.

Figure 1

Renin–Angiotensin System Pathway Overview. Angiotensinogen is the penultimate RAS precursor that is cleaved by renin to form Angiotensin I (AngI). Alternatively, AngI can also be formed through chymase-mediated metabolism converting Ang(1-12) to AngI. AngI can be metabolized to Angiotensin II (AngII) through angiotensin-converting enzyme (ACE) or chymase-mediated metabolism, where AngII binding onto AT1R promotes the classical arm of RAS leading to vasoconstriction, inflammation activation, and cardiac hypertrophy. AngII can be further metabolized to form Angiotensin III (AngIII) by APA (aminopeptidase A), where AngIII metabolism via APN (aminopeptidase N) can form Angiotensin IV (AngIV), an AT4R agonist. Alternatively, AngII can form through NEP (neprilysin), PEP (prolyl endo-peptidase), and THOP (thimet oligopeptidase) mediated metabolism. Ang(1-7) is formed by (1) metabolism of AngII by ACE2, PEP, or PRCP (pro-X carboxypeptidase) or (2) an alternative pathway where Ang(1-9) can be metabolized by ACE, NEP, and PEP activity. Ang(1-7) can be metabolized to Ang(1-5) or Alamandine (AAng(1-7)) by ACE and AD (aspartate decarboxylase), respectively. AAng(1-7) can also be formed through AngII breakdown into AngA via AD, followed by AngA metabolism via ACE2. Ang(1-7) and Ang(1-5) can both bind onto MasR to counteract AT1R activation. AAng(1-7) binding onto MrgD, a Mas-related GPCR, can lead to vasodilation in the heart and kidney. Ang(3-7) can be formed by either (1) cleavage of AngIV by carboxypeptidase P (Carb-P) and prolyl oligopeptidase (PO) or by (2) dipeptidyl peptidase 3 (DPP3) cleavage of Ang(1-7). Red lines show the three RAS peptides that can being onto AT1R to activate the classical RAS pathway. Blue lines indicate peptide binding to anti-inflammatory signaling receptors AT2R, MasR, MrgD). Gray lines represent peptide binding onto the AT4R; the effects of this activation are currently not well delineated.