Imbalance between endothelial progenitors cells and microparticles in HIV-infected patients naive for antiretroviral therapy
da Silva, Erika F.R.a; Fonseca, Francisco A.H.b; França, Carolina N.b; Ferreira, Paulo R.A.a; Izar, Maria C.O.b; Salomão, Reinaldoa; Camargo, Luciano M.b; Tenore, Simone B.a; Lewi, David S.a
aInfectious Diseases Division
bLipids, Atherosclerosis and Vascular Biology Section, Cardiovascular Division, Federal University of São Paulo, Sao Paulo, Sao Paulo, Brazil.
Correspondence to Erika F.R. da Silva, MD, PhD, R. Loefgren 1588, Vl. Clementino, Sao Paulo, SP 04040 002, Brazil. Tel/fax: +55 11 5575 1104/5081 7942/5573 5081; e-mail: firstname.lastname@example.org,email@example.com.
Received 10 December, 2010
Revised 28 April, 2011
Accepted 3 June, 2011
Background: Cardiovascular events have been reported among HIV-infected patients following antiretroviral therapy. However, the role of HIV itself in determining vascular damage is less described. Chronic inflammatory state might impair some regulatory endothelium properties leading to its activation, apoptosis or erosion.
Objectives: To evaluate the balance between endothelial progenitor cells and microparticles in HIV-infected antiretroviral drug-naive patients.
Design: A case–control study comparing HIV-infected patients (n = 35) with sex-matched and age-matched healthy controls (n = 33).
Methods: Endothelial progenitor cells populations expressing CD34+, CD133+ and KDR+ were quantified by flow cytometry. Endothelial-derived microparticles, expressing CD51+, and platelet-derived microparticles, expressing CD31+/CD42+, were also measured. Endothelial function was estimated by flow-mediated dilation.
Results: Lower percentages of endothelial progenitor cells (CD34+/KDR+) were observed in HIV-infected individuals compared with controls (0.02 vs. 0.09%, P = 0.045). In addition, endothelial microparticles concentration was higher in HIV-infected individuals (1963 vs. 436 microparticles/μl platelet-poor plasma, P = 0.003), with similar number of platelet-derived microparticles among groups. Furthermore, flow-mediated dilation was lower among HIV-infected individuals compared with controls [mean (SEM): 10 (1) and 16% (2), respectively; P = 0.03].
Conclusion: Our findings suggest an imbalance between endothelial progenitor cells mobilization and endothelial apoptosis. The alteration in the turnover of endothelial cells may contribute to cardiovascular events in HIV-infected patients.
The possible contribution of HIV infection and its inflammatory state to cardiovascular events has been supported by some studies [1,2]. Although HIV and antiretroviral treatment are associated with metabolic complications (insulin resistance, hypertriglyceridemia and increased truncal adiposity), it is also possible that HIV itself has a direct role on cardiovascular disease (CVD) . Increasing importance has been given to studies published in recent years evaluating the potential role of HIV infection itself on CVD, independently of the classical risk factors [1,2]. Coronary artery disease results from a chronic inflammation of the vascular wall leading to vessel occlusion and organ damage . Inflammation can promote cell damage or impair healthy turnover of vascular cells [4,5]. Using specific markers, it is now possible to quantify the amount of blood endothelial progenitor cells (EPCs) and plasma microparticles, allowing new understanding of the balance between apoptosis, erosion and replacement of endothelial cells [6–12]. The imbalance between EPCs and microparticles has already been identified among non-AIDS patients with classic risk factors (diabetes, hypertension, smokers), suggesting potential role on cardiovascular events [7,8,13–16].
HIV-infected patients exhibit increased rates of CVD compared with general population [17,18]. Although traditional cardiovascular risk factors have been shown to be common among patients with HIV [18–20], the role of inflammation and the utility of related biomarkers are less established in this population. Considering HIV infection as a chronic inflammatory disease with relatively high rates of cardiovascular events, we hypothesized that lower mobilization of EPCs and increased rates of endothelial apoptosis could be new mechanisms implicated on CVD seen among these patients. Therefore, this study aimed to evaluate EPCs and microparticles in HIV-infected antiretroviral drug-naive patients.
This is a cross-sectional study with patients selected consecutively. HIV-infected patients of both sexes, ages 20–60 years, from the outpatient clinic of the Division of Infectious Diseases of the Federal University of Sao Paulo were included in the study. Healthy age-matched and sex-matched controls of same socioeconomic background were prospectively included. Exclusion criteria were CVD (coronary heart disease, stroke, peripheral vascular disease), or current opportunist infection in the last 3 months, hypolipidemic therapy, diabetes, renal failure, heart failure, pregnancy and current or prior antiretroviral therapy. In addition, we excluded individuals with any pharmacologic therapy or comorbidities (except HIV) that could affect the levels of EPCs or microparticles [7,14]. The only concomitant therapy observed was antidepressant in two HIV patients. Written informed consent was obtained from all participants and the study protocol was approved by the Ethical Committee of the Federal University of São Paulo.
Clinical and laboratory measurements
Demographic data, standardized blood pressure measurements and anthropometric parameters were obtained from HIV-infected patients and controls. A chart review from the HIV-infected patients, including HIV duration, CD4+ cell count and HIV-RNA viral load were also collected.
Fasting (12-h) blood samples were obtained for biochemical analyses, which included lipid profile, glucose, high-sensitivity C-reactive protein (hsCRP) and apolipoprotein B.
Briefly, for EPC measurements, blood samples were collected in EDTA-containing tubes and the mononuclear cells were separated by Ficoll density gradient centrifugation (Ficoll Paque Plus; GE Healthcare Bio-Sciences AB, Upsala, Sweden). The cells were incubated for 30 min with the following mouse antibodies: CD34-FITC [BD Biosciences, Franklin Lakes, New Jersey, USA, (BD Biosciences, FL)], CD133-APC (Miltenyi Biotec, Auburn, Alabama, USA) and KDR-PE (R&D Systems, Minneapolis, Minnesota, USA) (Fig. 1a). As controls for unspecific staining, the corresponding isotype-matched controls were used: IgG1-FITC (BD Biosciences, FL), IgG1-PE (R&D Systems) and IgG1-APC (Miltenyi Biotec). Immediately after this process, a minimum of 500.000 events was acquired in a four-color flow cytometer [FACSCalibur; BD Biosciences, San Jose, California, USA, (BD Biosciences, SJ)]. All the analyses were done with Cell Quest Pro software (BD Biosciences, SJ). EPCs were characterized as CD34+/KDR+ (Fig. 1a) and expressed as percentage (%) of total progenitor cells in the lymphocyte gate. For platelet-derived microparticle (PMP) and endothelial-derived microparticle (EMP) quantification, the blood sample was collected in a citrate tube and centrifuged to obtain the platelet-rich plasma (PRP). The PRP was then centrifuged to get the platelet-poor plasma (PPP). PPP was incubated for 20 min with the mouse antibodies CD51-FITC (BD Biosciences, FL) for EMP identification (Fig. 1b) without staining in FL2 and with CD42-FITC and CD31-PE (BD Biosciences, FL) for PMP identification (Fig. 1c). CD51 has been proposed as specific for endothelial cells, obviating a need for a second antibody test [21–25]. Isotypes IgG1-FITC (BD Biosciences, FL) and IgG1-PE (BD Biosciences, FL) were used as controls. Microparticles were expressed as a concentration in microliters of PPP (microparticles/μl plasma). TruCOUNT tubes (BD Biosciences, FL) were used to estimate the microparticles count.
Endothelial function was estimated by brachial flow-mediated dilation (FMD) measured in the morning after an overnight fast using standard technique . Briefly, after a 10–15-min rest, the brachial artery in the right antecubital fossa was visualized using a linear transducer. The device used for ultrasound/echocardiography was a Hewlett Packard Sonos 5500, coupled with a linear transducer with a frequency of up to 11 MHz with simultaneous monitoring of electrocardiogram (ECG). Once the optimal image of the artery was achieved, the baseline vessel diameter was measured. Reactive hyperemia was induced by inflating the blood pressure cuff to 200 mmHg, or at least 50 mmHg above SBP, on the distal forearm for 5 min and then deflating the cuff. End-diastolic images were obtained at the time of onset of the QRS complex on ECG. These images were acquired at baseline and 1 min after cuff deflation. The percentage change from the baseline diameter to the value detected during reactive hyperemia was calculated to determine FMD. The intrasonographer and intersonographer variability was less than 1 and less than 2%, respectively.
Data are presented as means and SD, unless otherwise specified. Groups were compared by Student's t-test for independent samples or by nonparametric Mann–Whitney U-test, when appropriate. Categorical variables were compared using Pearson's χ2-test. Correlations between EPCs, microparticles and hsCRP were examined by the nonparametric Spearman's rank correlation test. All tests were two tailed and the level of significance was set at a P value less than 0.05. All analyses were performed using SPSS software, version 16 (SPSS Inc., Chicago, Illinois, USA).
Sixty-eight volunteers (35 HIV-positive patients and 33 controls), aged from 21 to 48 years (median 33 years), with 80% men of mixed racial background were included. Demographic characteristics of the study population are presented in Table 1, and did not differ between groups. Total cholesterol and high-density lipoprotein-cholesterol (HDL-c) were lower in HIV-infected patients, without differences in other laboratory parameters (Table 2). In the HIV-infected group, the mean time from diagnosis was 3.8 years, mean CD4+ cell count was 590 cells/μl and mean viral load was 20.515 copies/ml (mean log 3.76).
Endothelial progenitor cells and microparticles
The percentage of EPCs [mean (SD)] was lower in HIV-infected patients when compared with controls for CD34+/KDR+ cells [0.02 (0.01) vs. 0.09% (0.03), P = 0.045]; without differences for cells expressing CD34+/CD133+ [0.01 (0.02) vs. 0.01% (0.02), P = 0.25] or KDR+/CD133+ [0.01 (0.02) vs. 0.01% (0.03), P = 0.21] (Fig. 2). In addition, higher number of EMP was observed among HIV-infected patients compared with controls [1963 (62) vs. 436 microparticles/μl (30) PPP, P = 0.003] (Fig. 3). The amount of PMP was similar between groups [24 992 vs. 26 642 microparticles/μl PPP in HIV-infected patients and controls, respectively, (P = 0.83)].
The observed FMD was lower among HIV-infected patients when compared with controls [mean (SEM): 10 (1) and 16% (2), P = 0.03, unpaired Student's t-test]. We found a negative correlation for hsCRPs and EPCs (KDR+/CD133, P = 0.029, Spearman's rank correlation test), but not for other EPC subpopulations or microparticles. No correlations were found between microparticles and FMD (data not shown).
The major contribution of our study was the observation that among HIV-infected antiretroviral drug-naive patients, there is an imbalance between the mobilization of EPCs and microparticles derived from the endothelium, as well as impairment on endothelial function. These findings may be related to the early development of CVD in this population, as already seen in the Strategies for Management of Antiretroviral Therapy (SMART) clinical trial with patients not receiving antiretroviral therapy . In fact, the mechanisms of atherosclerosis related to classic risk factors such as hypertension, smoking or diabetes have in common endothelial dysfunction . These findings open interesting perspectives for investigation of cellular mechanisms involving infection, inflammation and apoptosis of endothelial cells and a decreased reparative capacity, owing to the reduced percentage of EPCs in plasma .
The imbalance between EMPs and EPCs cannot be explained by differences in the prevalence of the classical cardiovascular risk factors, suggesting that the HIV infection itself may be related to the alterations observed in the turnover of endothelial cells. In fact, the only cardiovascular risk factor observed in the HIV-infected group was dyslipidemia characterized mainly by low HDL-c, a typical finding in antiretroviral drug-naive patients, in which a detectable viral load and inflammation coexist .
High levels of hsCRP, a marker of inflammation, are associated with increased cardiovascular risk in non-HIV-infected population and might be a better predictor of risk than low-density lipoprotein cholesterol levels in some populations . According to the JUPITER (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin) trial , hsCRP can identify individuals under risk even with relatively normal cholesterol levels. Triant et al. demonstrated in a retrospective study that high levels of hsCRP and HIV infection are associated with a two-fold increase in the risk of myocardial infarction. In our study, the average hsCRP was 1.64 and 1.18 mg/l in the HIV-infected and control groups, respectively, values which are near to those reported by Baker et al. among antiretroviral drug-naive patients. These values are below the cutoff values for hsCRP associated with cardiovascular risk, suggesting that our finding of imbalance between EMPs and EPCs could be related to the viral infection itself.
Since 1997, when Asahara et al. isolated an angioblast from human peripheral blood of adults, which differentiate in vitro into endothelial cells, new important concepts on the turnover of endothelial cells were discovered. The so-called EPC has been characterized by surface markers CD34 and vascular endothelial growth factor receptor-2 (VEGFR2 or KDR in humans). Immature subset of EPCs expresses the surface marker CD133 . The expression of CD34, VEGFR2 and CD133 is typically found on angioblasts and demonstrates the immature nature of these cells . Reduced number of EPCs has been reported in patients at risk of cardiovascular events, including acute myocardial infarction and stroke [7,8].
We have chosen HIV-infected patients not previously exposed to antiretroviral therapy in order to address the influence of HIV itself on the EPCs and microparticles. The literature has well described the influence of antiretroviral therapy on endothelial function, metabolic alterations (dyslipidemia), inflammation and the development of a high cardiovascular risk due to this exposure [1,2,33]. Currently, there are only preliminary results about EPCs and microparticles in HIV-infected patients. Papasavvas et al. evaluated EPCs in 66 HIV-infected patients (nine antiretroviral drug-naive patients) and in 50 controls. The HIV-infected patients had higher percentages of EPCs (CD34+/ KDR+) in two measures during a 1-year follow-up compared with controls. These findings are in contrast with our results, reporting lower levels of EPCs in HIV-infected antiretroviral drug-naive patients. This research did not address comorbidities that could influence the level of EPCs and microparticles, as statins use, for example, in this population. After the introduction of antiretroviral treatment, with virological control, there is a decrease in markers of the inflammatory state, such as hsCRP, preceding the development of metabolic alterations [35,36]. Thus, the use of antiretroviral treatment could affect microparticles and EPCs by multiple mechanisms. Thus, one of the most important characteristics of our study was the avoidance of such confounders, examining HIV-infected patients naive of antiretroviral therapy.
Microparticles have been defined as small vesicular structures with less than 1 μm formed from the plasma membranes of diverse cell types in response to activation, injury and/or apoptosis . Most of microparticles detected in blood originates from platelets, but other cells such as leucocytes, erythrocytes and endothelial and even malignant cells could also shed microparticles [38–40]. They express on their surface antigens of the cell from which they originated, allowing their characterization . Microparticles are released from cell membranes by triggers such as cytokines, thrombin, endotoxins, hypoxia and shear stress capable of inducing activation or apoptosis [3,12]. In healthy persons, EMP represents a minority of total microparticles. Overproduction of microparticles has been related to various physiological and pathophysiological conditions [24,40,41]. Moreover, it is unclear whether increased microparticles are cause or a consequence of vascular disease states because cardiovascular-related factors, such as metabolic disturbances, cytokines and possibly infectious agents can trigger microparticles production . There are few studies reporting the levels of microparticles among HIV-infected patients. Corrales-Medina et al. found higher number of PMP among HIV-infected patients compared with controls. In the evaluation of PMP, we found no difference between groups. It is possible that some characteristics of this cohort could explain these differences, mainly the relatively good immunity and low viral load. Conversely, we found a significant increase in the EMP in the HIV-infected group compared with control. We did not find previous studies reporting the increased number of EMP on HIV-infected patients. Furthermore, EMP has been proposed as new biomarker of endothelial dysfunction [15,41], and increased number of EMP was reported in high-risk patients with uncontrolled risk factors and CVD .
We observed that HIV-infected patients had lower FMD compared with controls. These data are corroborated by several studies that showed impairment in FMD among HIV-infected patients ranging from 5.1 to 8.8% [33,35,36,44–46]. The literature has shown that endothelial dysfunction is an independent predictor of cardiovascular events . These changes in patients not yet exposed to antiretroviral and in the absence of other classic risk factors for CVD suggest a role of HIV itself as a causative agent of endothelial dysfunction.
The mechanisms by which HIV decreases the number of EPCs and increases EMP remain to be determined. HIV replication may activate endothelial surfaces directly or via upregulation of proinflammatory cytokines [47,48]. Endothelial activation can lead to vessel damage and apoptosis with release of EMP.
Reduced numbers of EPCs independently predict future cardiovascular events, thus supporting an important role for HIV itself as a cardiovascular risk factor [7,8]. This new finding in HIV-infected antiretroviral drug-naive patients may be associated with increased cardiovascular risk in the long-term follow-up, after the introduction of antiretroviral therapy and subsequent development of metabolic alterations. It could be aggravated in the future with the need of antiretroviral therapy and subsequent development of hyperlipidemia. On the contrary, the impact of early antiretroviral therapy on the turnover of endothelial cells emerges as a promising therapy for the prevention of premature CVD in these patients.
Our results showing an imbalance between EPCs and microparticles should be considered as preliminary results based on the relatively small sample size and its transversal, case–control design. However, these findings seem important to explain the high rates of premature CVD among HIV-infected patients. Further studies with longer follow-up addressing EPCs and EMPs are needed.
Conflicts of interest
This study was supported by FAPESP (São Paulo Research Foundation) grant 2008/55223-6. E.F.R.S. is a recipient of a research grant from CAPES (Coordination for the Improvement of Higher Level – or Education – Personnel). Besides this funding disclosure, the authors have no conflicts of interest to declare.
E.F.R.S. designed the study, made the acquisition and interpretation of data (clinical and laboratory), wrote the manuscript and approved the final version for the publication.
F.A.H.F. made a contribution to the conception of the design, data interpretation, revised the manuscript and approved the final version for the publication.
C.N.F. made all the acquisition, analysis and interpretation of flow cytometry, revised the manuscript and approved the final version for the publication.
P.R.A.F. made all the statistical analyses and interpretation of data, revised the manuscript and approved the final version for the publication.
M.C.O.I. reviewed the statistical analysis and interpretation of data, revised the manuscript and approved the final version for the publication.
R.S. made all the pilot analysis and interpretation of the flow cytometry data, revised the manuscript and approved the final version for the publication.
L.M.C. made a contribution to the acquisition and interpretation of FMD data and approved the final version for the publication.
S.B.T. made a contribution to the acquisition and interpretation of clinical data and approved the final version for the publication.
D.S.L. made a contribution to the conception of the study, interpretation and analysis of data, revised the manuscript and approved the final version for the publication.
Data presented previously at the 14th International Congress on Infectious Diseases, 9–12 March 2010, Miami, Florida, USA (published in the Annals of the 14th International Congress on Infectious Diseases) and at the XXXI Congresso da Sociedade de Cardiologia do Estado de São Paulo, 29 April to 5 May 2010, Sao Paulo, Sao Paulo, Brazil (published in Suplemento Especial da Revista da Sociedade de Cardiologia do Estado de São Paulo).
1. Lo J, Grinspoon S. Cardiovascular disease in HIV-infected patients: does HIV infection in and of itself increase cardiovascular risk?. Curr Opin HIV AIDS 2008; 3:207–213.
2. Carr A. Pathogenesis of cardiovascular disease in HIV infection. Curr Opin HIV AIDS 2008; 3:234–239.
3. Ross R. Atherosclerosis as an inflammatory disease. N Engl J Med 1999; 340:115–126.
4. Choy JC, Granville DJ, Hunt DW, McManus BM. Endothelial cell apoptosis: biochemical characteristics and potential implications for atherosclerosis. J Mol Cell Cardiol 2001; 33:1673–1690.
5. Gill M, Dias S, Hattori K, Rivera ML, Hicklin D, Witte L, et al. Vascular trauma induces rapid but transient mobilization of VEGFR2(+)AC133(+) endothelial precursor cells. Circ Res 2001; 88:167–174.
6. Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 1999; 85:221–228.
7. Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 2001; 89:E1–E7.
8. Werner N, Nickening G. Clinical and therapeutical implications of EPC biology in atherosclerosis. J Cell Mol Med 2006; 10:318–322.
9. Ria R, Piccoli C, Cirulli T, Falzetti F, Mangialardi G, Guidolin D, et al. Endothelial differentiation of hematopoietic stem and progenitor cells from patients with multiple myeloma. Clin Cancer Res 2008; 14:1678–1685.
10. Hristov M, Erl W, Weber PC. Endothelial progenitor cells. Mobilization, differentiation and homing. Arterioscler Thromb Vasc Biol 2003; 23:1185–1189.
11. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275:964–967.
12. Martínez MC, Tesse A, Zobairi F, Andriantsitohaina R. Shed membrane microparticles from circulating and vascular cells in regulating vascular function. Am J Physiol Heart Circ Physiol 2005; 288:H1004–H1009.
13. Verma S, Kuliszewski MA, Li SH, Szmitko PE, Zucco L, Wang CH, et al. C-reactive protein attenuates endothelial progenitor cell survival, differentiation, and function: further evidence of a mechanistic link between C-reactive protein and cardiovascular disease. Circulation 2004; 109:2058–2067.
14. Chironi GN, Boulanger CM, Simon A, Dignat-George F, Freyssinet JM, Tedgui A. Endothelial microparticles in diseases. Cell Tissue Res 2009; 335:143–151.
15. Mostefai HA, Andriantsitohaina R, Martínez MC. Plasma membrane microparticles in angiogenesis: role in ischemic diseases and in cancer. Physiol Res 2008; 57:311–320.
16. Pearson JD. Endothelial progenitors cells: an evolving story. Microvasc Res 2010; 79:162–168.
17. Currier JS, Taylor A, Boyd F, Dezii CM, Kawabata H, Burtcel B, et al. Coronary heart disease in HIV-infected individuals. J Acquir Immune Defic Syndr 2003; 33:506–512.
18. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab 2007; 92:2506–2512.
19. Hadigan C, Meigs JB, Corcoran C, Rietschel P, Piecuch S, Basgoz N, et al. Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clin Infect Dis 2001; 32:130–139.
20. Friis-Møller N, Weber R, Reiss P, Thiébaut R, Kirk O, d’Arminio Monforte A, et al. DAD study group. Cardiovascular disease risk factors in HIV patients-association with antiretroviral therapy. Results from the DAD study. AIDS 2003; 17:1179–1193.
21. Arteaga RB, Chirinos JA, Soriano AO, Jy W, Horstman L, Jimenez JJ, et al. Endothelial microparticles and platelet and leukocyte activation in patients with the metabolic syndrome. Am J Cardiol 2006; 98:70–74.
22. Sabatier F, Roux V, Anfosso F, Camoin L, Sampol J, Dignat-George F. Interaction of endothelial microparticles with monocytic cells in vitro induces tissue factor-dependent procoagulant activity. Blood 2002; 99:3962–3970.
23. Mutin M, Dignat-George F, Sampol J. Immunologic phenotype of cultured endothelial cells: quantitative analysis of cell surface molecules. Tissue Antigens 1997; 50:449–458.
24. Burnier L, Fontana P, Kwak BR, Angelillo-Scherrer A. Cell-derived microparticles in haemostasis and vascular medicine. Thromb Haemost 2009; 101:439–451.
25. Dignat-George F, Boulanger CM. The many faces of endothelial microparticles. Arterioscler Thromb Vasc Biol 2011; 31:27–33.
26. Brandão SA, Izar MC, Fischer SM, Santos AO, Monteiro CM, Póvoa RM, et al. Early increase in autoantibodies against human oxidized low-density lipoprotein in hypertensive patients after blood pressure control. Am J Hypertens 2010; 23:208–214.
27. The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006; 355:2283–2296.
28. Blann AD. Endothelial cell activation, injury, damage and dysfunction: separate entities or mutual terms?. Blood Coagul Fibrinolysis 2000; 11:623–630.
29. Riddler SA, Smit E, Cole SR, Li R, Chmiel JS, Dobs A, et al. Impact of HIV infection and HAART on serum lipids in men. JAMA 2003; 289:2978–2982.
30. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002; 347:1557–1565.
31. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. JUPITER Trial Study GroupReduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009; 373:1175–1182.
32. Baker J, Ayenew W, Quick H, Hullsiek KH, Tracy R, Henry K, et al. High-density lipoprotein particles and markers of inflammation and thrombotic activity in patients with untreated HIV infection. J Infect Dis 2010; 201:285–292.
33. Oliviero U, Bonadies G, Apuzzi V, Foggia M, Bosso G, Nappa S, et al. Human immunodeficiency virus per se exerts atherogenic effects. Atherosclerosis 2009; 204:586–589.
34. Papasavvas E, Hsue P, Reynolds G, Pistilli M, Hancock A, Martin JN, et al.Increased endothelial precursor cells are not associated with carotid intima-media thickness progression in chronically HIV-1-infected subjects [abstract #701]. In: Proceedings of the 17th Conference on Retrovirus and Opportunistic Infections (CROI); 16–19 February 2010; San Francisco, California, USA.
35. Maggi P, Quirino T, Ricci E, De Socio GVL, Gadaleta A, Ingrassia F, et al. Cardiovascular risk assessment in antiretroviral-naive HIV patients. AIDS Patient Care STDS 2009; 23:809–813.
36. van Wijk JP, de Koning EJ, Cabezas MC, Joven J, op’t Roodt J, Rabelink TJ, et al. Functional and structural markers of atherosclerosis in human immunodeficiency virus-infected patients. J Am Coll Cardiol 2006; 47:1117–1123.
37. Hugel B, Martínez MC, Kunzelmann C, Freyssinet JM. Membrane microparticles: two sides of the coin. Physiology (Bethesda) 2005; 20:22–27.
38. Amabile N, Rautou PE, Tedgui A, Boulanger CM. Microparticles: key protagonists in cardiovascular disorders. Semin Thromb Hemost 2010; 36:907–916.
39. Heiss C, Amabile N, Lee AC, Real WM, Schick SF, Lao D, et al. Brief secondhand smoke exposure depresses endothelial progenitor cells activity and endothelial function: sustained vascular injury and blunted nitric oxide production. J Am Coll Cardiol 2008; 51:1760–1771.
40. Shai E, Varon D. Development, cell differentiation, angiogenesis: microparticles and their roles in angiogenesis. Arterioscler Thromb Vasc Biol 2011; 31:10–14.
41. Boulanger CM, Amabile N, Tedgui A. Circulating microparticles: a potential prognostic marker for atherosclerotic vascular disease. Hypertension 2006; 48:180–186.
42. Puddu P, Puddu GM, Cravero E, Muscari S, Muscari A. The involvement of circulating microparticles in inflammation, coagulation and cardiovascular diseases. Can J Cardiol 2010; 26:140–145.
43. Corrales-Medina VF, Simkins J, Chirinos JA, Serpa JA, Horstman LL, Jy W, et al. Increased levels of platelet microparticles in HIV-infected patients with good response to highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2010; 54:217–218.
44. Andrade AC, Ladeia AM, Netto EM, Mascarenhas A, Cotter B, Benson CA, et al. Cross-sectional study of endothelial function in HIV-infected patients in Brazil. AIDS Res Hum Retroviruses 2008; 24:27–33.
45. Blanco JJ, Garcia IS, Cerezo JG, de Rivera JM, Anaya PM, Raya PG, et al. Endothelial function in HIV-infected patients with low or mild cardiovascular risk. J Antimicrob Chemother 2006; 58:133–139.
46. Spagnoli LG, Bonanno E, Sangiorgi G, Mauriello A. Role of inflammation in atherosclerosis. J Nucl Med 2007; 48:1800–1815.
47. Ren Z, Yao Q, Chen C. HIV-1 envelope glycoprotein 120 increases intercellular adhesion molecule-1 expression by human endothelial cells. Lab Invest 2002; 82:245–255.
48. Bussolino F, Mitola S, Serini G, Barillari G, Ensoli B. Interactions between endothelial cells and HIV-1. Int J Biochem Cell Biol 2001; 33:371–390.
This article has been cited 4 time(s).
AIDS Research and Human RetrovirusesProangiogenic Hematopoietic Cells In Acute HIV InfectionAIDS Research and Human Retroviruses
Trends in Cardiovascular MedicineCirculating endothelial progenitor cells in HIV infection: A systematic reviewTrends in Cardiovascular Medicine
Endothelial Dysfunction in HIV Infection - The Role of Circulating Endothelial Cells, Microparticles, Endothelial Progenitor Cells and Macrophages
AIDS Reviews, 14(4):
Thrombosis ResearchEffect of antiviral therapy on pro-angiogenic hematopoietic and endothelial progenitor cells in HIV-infected peopleThrombosis Research
endothelial progenitor cells; endothelial-derived microparticles; HIV infection; inflammation; platelet-derived microparticles
© 2011 Lippincott Williams & Wilkins, Inc.
Highlight selected keywords in the article text.