Azidothymidine (AZT) leads to arterial stiffening and intima-media thickening in mice

Abstract

HIV positive patients on highly active antiretroviral therapy (HAART) have shown elevated incidence of a number of non-AIDS defining co-morbidities, including cardiovascular disease. Given that HAART regimens contain a combination of at least three drugs, that disease management often requires adjustment of these regimens, and HIV, independent of HAART, also plays a role in development of co-morbidities, determining the role of specific HAART drugs and HIV infection itself from clinical data remains challenging. To characterize specific mediators and underlying mechanisms of disease, in vitro and in vivo animal models are required, in parallel with clinical data. Given its low cost azidothymidine (AZT) contributes to the backbone of a large proportion of HAART treated patients in the developing world where much of the global burden of HIV resides. The goal of this study was to test the hypothesis that AZT can lead to proatherogenic changes including the subclinical markers of arterial stiffening and intima-media thickening in mice. AZT (100 mg/kg) or vehicle was administered to wild-type FVB/N mice via oral gavage for 35 days. Cylindrical biaxial biomechanical tests on the common carotid arteries and suprarenal aortas exhibited arterial stiffening in AZT mice compared to controls. Multiphoton microscopy and histology demonstrated that AZT led to increased intima-media thickness. These data correlated with decreased elastin content and increased protease activity as measured by cathepsin zymography; no differences were observed in collagen content or organization, in vivo axial stretch, or opening angle. Thus, this study suggests the drug AZT has significant effects on the development of subclinical markers of atherosclerosis.

Monocyte-derived macrophage assisted breast cancer cell invasion as a personalized, predictive metric to score metastatic risk

“…Therefore, it may be that an important contribution to the variability in breast cancer cell invasion and tumor growth and spread may be due to the TAMs that infiltrate, and locally secrete cathepsins and cystatin C that can directly assist cancer cell invasion. As a predictive metric, this holds promise by providing insight into the importance of biomarkers in the local tumor microenvironment as opposed to studies that have sought metastatic correlation after serum measurement of cathepsins or cystatin C 51 52 53 . Cathepsins in serum may be from a number of sources, including cardiovascular sources for which cathepsin levels have been correlated with atherosclerosis, diabetes, and abdominal aortic aneurysms 54 55 .…”

Zidovudine (AZT) and Hepatic Lipid Accumulation: Implication of Inflammation, Oxidative and Endoplasmic Reticulum Stress Mediators

“…Zidovudine (3-azido-3′-deoxythymidine or AZT), a nucleoside reverse transcriptase inhibitor, was the first HAART drug approved by the U.S. Food and Drug Administration for treatment of patients with AIDS, and is still the backbone of the large proportion of HAART treated patients in the developing world where majority of HIV infected patients resides [4]. However, the clinical effectiveness of AZT is constrained due to its adverse side effects [5]; the most common of which is hepatotoxicity [6], [7].…”

Low-Cost Method to Monitor Patient Adherence to HIV Antiretroviral Therapy Using Multiplex Cathepsin Zymography

“…One HIV-negative control patient was loaded in each zymogram for normalization across gels. The initial hypothesis was that HIV-positive individuals on ART would have higher cathepsin activity in support of the data that ART leads to increased cardiovascular disease (21, 22), and cathepsins are elevated in cardiovascular disease (14–20). However, the results clearly indicated that a majority of the patients on ART had suppressed cathepsin activity compared to the HIV-positive, ART naïve patients or the HIV-negative control, as shown in the representative zymogram by the cleared white bands that indicate active cathepsins (Figure 1A).…”