Several reports suggest that HIV infected individuals present signs of accelerated vascular aging including atherosclerosis (AS). Available data suggest that the immune dysregualtion associated with HIV infection, not completely restored by the use of combination antiretroviral therapy (cART), plays a role in AS. However, cART directly or indirectly may also play an important role in AS. It has been suggested that the following four events during the aging process are key to evoke AS; 1) Telomere (TL) shortening-mediated DNA damage and apoptosis, 2) impairment of vascular reactivity, 3) inflammation, and 4) impairment of efferocytosis (phagocytosis). In this regard, our group has reported that p90RSK-ERK5 module plays a crucial role in endothelial (EC) dysfunction. Our preliminary data show that cART-induced p90RSK activation inhibited ERK5 transcriptional activity and cART also increased sCD40L plasma levels. Interestingly, sCD40L also increase the activation of p90RSK. Furthermore cART-induced p90RSK activation inhibited ERK5 transcriptional activity thus decreased M? efferocytosis. Lastly, we found that cART caused TL shortening via p90RSK activation, leading to DNA damage and apoptosis. Both increased apoptosis and impairment of efferocytosis evoke secondary stress responses via releasing cellular components including cell-free DNA (cfDNA) and high mobility group box 1 (HMGB1). Based on the rationale above, we propose a novel hypothesis centered on p90RSK activation which provides a link, not previously described, to several observations suggesting an association between cART and accelerated AS in HIV infected individuals. We will test this hypothesis in a 3- year longitudinal study of 180 HIV+ individuals (viral load d50 c/ml) aged e 50 years who are therefore at increased risk of developing measurable changes in markers of AS such as carotid intima-media thickness (CIMT) and carotid artery stiffness (CAS). 90 HIV- controls will be matched for age, gender and Reynolds CVD risk score. We will assess the effect of cART and sCD40L on p90RSK in participants-derived monocytes and secondary stress responses both in monocytes (HMGB1) and plasma (HMGB1, 8-OHdG). We will further define the causal effect of cART and sCD40L on p90RSK-induced accelerated aging of EC and M? in animal studies.
Specific Aims :
AIM 1. To determine whether chronic exposure to cART and elevated plasma levels of sCD40L in older HIV infected individuals are associated with p90RSK activation leading to enhanced aging of monocytes (reduce telomere length, reduced efferocytosis) and whether these measures of monocyte aging are associated with markers of atherosclerosis (CIMT and CAS).
AIM 2. To determine whether the markers of secondary stress response (monocytic and plasma levels of HMGB1, plasma levels of 8-hydroxy-2'- deoxyguanosine (8-OHdG)) in cART-treated older HIV infected individuals are associated with measures of CIMT and CAS.
AIM 3. To determine in vitro and in small animal models, the causal effect of cART and sCD40L on p90RSK activation leading to cellular aging of EC and M? which underlie AS.
Over a million people are thought to be HIV infected in the US and it is projected that by 2015 more than half of all HIV+ individuals will be over the age of 50. However, aging is associated with progression of atherosclerosis (AS), which leads to cardiovascular and cerebrovascular disease. Although several reports have suggested that combination antiretroviral therapy (cART) is associated directly and indirectly with premature senescence and subsequent AS, how key events in AS are affected by cART is not well known. Our proposal is centered on the effect of cART and sCD40L on p90RSK-ERK5 module which by affecting the function of both endothelial cells and macrophages leads to AS. The information acquired will inform us on preventive strategies for AS that can be developed in older HIV infected individuals.
| Nayak, Rohit; Schifitto, Giovanni; Doyley, Marvin M (2018) Visualizing Angle-Independent Principal Strains in the Longitudinal View of the Carotid Artery: Phantom and In Vivo Evaluation. Ultrasound Med Biol 44:1379-1391 |
| Ahmed, Rifat; Gerber, Scott A; McAleavey, Stephen A et al. (2018) Plane-Wave Imaging Improves Single-Track Location Shear Wave Elasticity Imaging. IEEE Trans Ultrason Ferroelectr Freq Control 65:1402-1414 |
| Le, Nhat-Tu; Abe, Jun-Ichi (2018) MicroRNA 199a and the eNOS (Endothelial NO Synthase)/NO Pathway. Arterioscler Thromb Vasc Biol 38:2278-2280 |
| Ko, Kyung Ae; Wang, Yin; Kotla, Sivareddy et al. (2018) Developing a Reliable Mouse Model for Cancer Therapy-Induced Cardiovascular Toxicity in Cancer Patients and Survivors. Front Cardiovasc Med 5:26 |
| Venkatesulu, Bhanu Prasad; Mahadevan, Lakshmi Shree; Aliru, Maureen L et al. (2018) Radiation-Induced Endothelial Vascular Injury: A Review of Possible Mechanisms. JACC Basic Transl Sci 3:563-572 |
| Ko, Kyung Ae; Fujiwara, Keigi; Krishnan, Sunil et al. (2017) En Face Preparation of Mouse Blood Vessels. J Vis Exp : |
| Connor, Ryan; Jones, Letitia D; Qiu, Xing et al. (2017) Frontline Science: c-Myc regulates P-selectin glycoprotein ligand-1 expression in monocytes during HIV-1 infection. J Leukoc Biol 102:953-964 |
| Le, Nhat-Tu; Martin, James F; Fujiwara, Keigi et al. (2017) Sub-cellular localization specific SUMOylation in the heart. Biochim Biophys Acta Mol Basis Dis 1863:2041-2055 |
| Mao, Yun; Luo, Wei; Zhang, Lin et al. (2017) STING-IRF3 Triggers Endothelial Inflammation in Response to Free Fatty Acid-Induced Mitochondrial Damage in Diet-Induced Obesity. Arterioscler Thromb Vasc Biol 37:920-929 |
| Nayak, Rohit; Huntzicker, Steven; Ohayon, Jacques et al. (2017) Principal Strain Vascular Elastography: Simulation and Preliminary Clinical Evaluation. Ultrasound Med Biol 43:682-699 |
Showing the most recent 10 out of 15 publications
