1.
Novel mediators of statin effects on plaque in HIV: a proteomics approach.
deFilippi, C, Lo, J, Christenson, R, Grundberg, I, Stone, L, Zanni, MV, Lee, H, Grinspoon, SK
AIDS (London, England). 2018;(7):867-876
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Abstract
OBJECTIVE HIV patients have increased atherosclerotic coronary vascular disease (ASCVD), thought to be mediated through inflammatory mechanisms. We hypothesized that among asymptomatic HIV-infected patients with subclinical coronary plaque, statin therapy would modulate unique inflammatory and cardiovascular proteins in relation to change in subclinical coronary plaque volume. We tested this hypothesis using a novel proteomics approach. DESIGN Forty HIV-infected participants were randomized to atorvastatin (40 mg/day) versus placebo, and underwent computed tomography coronary angiography to quantify plaque volume at baseline and 1 year. METHODS We used Olink Cardiovascular III and Cardiometabolic panels based on dual antibody epitope recognition with linked DNA amplification to compare change over time in 184 proteins in treatment versus placebo and in relation to change in coronary plaque volume. RESULTS Six proteins (TFPI, CCL24, NT-Pro BNP, MBL2, LTBR, PCOLCE) changed significantly in the atorvastatin versus placebo group, many in innate immune and other novel inflammatory pathways. Twenty-six proteins changed significantly in relationship to total coronary plaque volume over 1 year. Notably, many of these proteins changed only weakly in relationship to change in low-density lipoprotein (LDL). Overlapping these two broad discovery approaches, proteins involved in myocardial fibrosis/collagen formation and monocyte chemoattraction changed with statin treatment, in relationship to plaque volume, but not LDL. CONCLUSION This proof-of-concept study employing a proteomic discovery platform offers insight into statin effects on novel immune pathways relevant to ASCVD progression in HIV. Novel biomarker discovery may enhance precision medicine strategies to estimate the efficacy of targeted therapies to reduce ASCVD progression and events in HIV.
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Atorvastatin Reduces Circulating Osteoprogenitor Cells and T-Cell RANKL Expression in Osteoporotic Women: Implications for the Bone-Vascular Axis.
Rattazzi, M, Faggin, E, Buso, R, Di Virgilio, R, Puato, M, Plebani, M, Zaninotto, M, Palmosi, T, Bertacco, E, Fadini, GP, et al
Cardiovascular therapeutics. 2016;(1):13-20
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Abstract
AIM: Circulating osteoprogenitors and receptor activator of nuclear factor kappa-B ligand (RANKL) expression in immune cells have been implicated in the pathogenesis of osteoporosis and vascular calcification. The role played by statin therapy in the bone-vascular axis is unknown. METHODS Twenty naïve postmenopausal osteoporotic hypercholesterolemic women were treated with Atorvastatin 40 mg/day for 3 months. Gene expression analysis was performed to assess modification in osteoprotegerin (OPG)/RANK/RANKL expression in isolated T cells and monocytes. A flow cytometry analysis was used to study changes in the levels of circulating osteoprogenitor cells. RESULTS After 3 months of treatment, Atorvastatin significantly reduced total cholesterol and LDL-C, without affecting HDL-C and triglycerides. Among circulating bone and phosphocalcium homeostasis markers, we found a significant increase in OPG levels (P < 0.01) and a modest reduction in osteocalcin (OCN) (P < 0.05). We also observed a significant reduction in RANKL expression in T cells (P < 0.05). No differences were found in the expression of RANK in T cells and RANKL and RANK in monocytes. OPG expression was low in both immune cell types and was not affected by the treatment. As for circulating osteoprogenitors, we found a significant reduction of CD34(+) BAP(+) (P < 0.05) and CD34(+) OCN(+) BAP(+) (P < 0.05) cells. In vitro studies showed that Atorvastatin reduced RANKL expression in activated human T-lymphoblastoid cells (Jurkat cell line). CONCLUSIONS Three-month Atorvastatin treatment leads to a reduction in circulating osteoprogenitor cells and RANKL expression in T cells, as well as increase in OPG serum levels. These data suggest that statins could have protective effects in the bone-vascular axis.