Mechanical and structural effects of HIV-1 proteins and highly active antiretroviral therapy (HAART) drugs on murine arteries

Microstructure;Vascular mechanics;Atherosclerosis;HIV

Hansen, Laura Marie ; Biomedical Engineering

University:Georgia Institute of Technology

Department:Biomedical Engineering

关键词: Microstructure;    Vascular mechanics;    Atherosclerosis;    HIV;   

Others  :  https://smartech.gatech.edu/bitstream/1853/45791/1/hansen_laura_m_201212_phd.pdf

美国|英语

来源: SMARTech Repository

【 摘 要 】

The overall goals of this project were to develop microstructurally based constitutive models to characterize the mechanical behavior of arteries and to investigate the effects of HIV proteins and antiretroviral drugs on the microstructure and mechanical behavior. To this end we created several constitutive models in aim 1 using a rule of mixtures approach, investigated the role of viral proteins in aim 2 through the use a transgenic mouse model, and studied the effects of the antiretroviral drug AZT administered to mice in aim 3.It is well known that the local mechanical environment which cells experience mediates growth and remodeling and that subsequent growth and remodeling can change that mechanical environment. This remodeling includes changes in the content and organization of the constituents of arteries (collagen, elastin, and smooth muscle cells). The first aim thus created models that incorporated the content and organization of these constituents using a rule-of-mixtures approach. The models we developed were able to capture the mechanical behavior of the arteries as well as previously developed phenomenological models while providing more physical meaning to the parameters, some which can be measured experimentally for incorporation into future models.Aims 2 and 3 investigated the mechanical and microstructural changes to murine arteries in response to HIV proteins or the drug AZT.While the development of antiretroviral therapy has greatly increased the life expectancy of patients with HIV, a number of other complications and co-morbidities including cardiovascular disease have become apparent.While clinical data has implicated both the virus and the antiretroviral drugs as playing roles, this work addressed the need of investigating these effects in a controlled manner.Specifically we used mouse models and focused on the two subclinical markers of increased intima-media thickness and arterial stiffening. Aim 2 used a transgenic mouse that expressed most of the human HIV proteins.We observed both intima-media thickening and arterial stiffening in alignment with clinical data.Other changes that also support a proatherogenic phenotype included decreased elastin content and changes in cathepsin activity.Aim 3 administered the antiretroviral drug AZT to healthy mice and we also observed the same subclinical markers of atherosclerosis including intima-media thickening and arterial stiffening as well as the other proatherogenic changes of decreased elastin and changes in cathepsin activity.Several other parameters including axial behavior, opening angles, collagen content, and collagen fiber angles were also quantified. These were important to fully characterize the vessel and may also be incorporated in the future into the constitutive models developed in aim1.In conclusion, in aim 1 we developed a microstructurally based constitutive model of arteries that effectively captures the mechanical behavior and includes parameters that have more physical meaning and some of which are experimentally tractable.Aims 2 and 3 both observed several subclinical markers of atherosclerosis in mice that express HIV proteins or were given AZT, providing a good model for future work and suggesting that both the HIV virus and antiretroviral drugs may play roles in the development of atherosclerosis in HIV.