Human Genetic Evidence for Involvement of CD137 in Atherosclerosis

Söderström, Leif Å.; Gertow, Karl; Folkersen, Lasse; Sabater‐Lleal, Maria; Sundman, Eva; Sheikine, Yuri; Goel, Anuj; Baldassarre, Damiano; Humphries, Steve E.; Fairé, Ulf dé; Watkins, Hugh; Tremoli, Elena; Veglia, Fabrizio; Hamsten, Anders; Hansson, Göran K.; Olofsson, Peder S.

doi:10.2119/molmed.2014.00004

Cited by 9 publications

(7 citation statements)

References 41 publications

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“…A survey of the literature suggests that of the 30 changes specific for SPS, 18 promote, or are associated with, atherosclerosis38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 (Table 2). The same is true for 12 of the 31 changes occurring in patients with both SPS and reduced GFR60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 and for 10 of the 27 changes specific for reduced mGFR72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 (Table 2). These results are compatible with the observations that the majority of the causes of morbidity and death in both patients with SPS and/or reduced GFR represent manifestations of cardiovascular disorders 6, 7, 8, 9, 14.…”

Section: Discussionmentioning

confidence: 69%

Shrunken Pore Syndrome Is Associated With Increased Levels of Atherosclerosis-Promoting Proteins

Almén

Björk

Nyman

et al. 2019

Kidney International Reports

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IntroductionShrunken pore syndrome (SPS), originally defined by cystatin C−based estimated glomerular filtration rate (eGFRcystatin C) being less than 60% of creatinine-based estimated glomerular filtration rate (eGFRcreatinine) in the absence of extrarenal influences on the plasma levels of cystatin C or creatinine, is associated with a high increase in mortality, even in the absence of reduced glomerular filtration rate (GFR). The objective of the present study was to determine whether the proteome of patients with SPS shows differences from that of patients with normal or reduced measured GFR (mGFR) without SPS.MethodsFour patient cohorts were included: 1 cohort with normal mGFR without SPS, 1 with normal mGFR with SPS, 1 with reduced mGFR without SPS, and 1 with reduced mGFR with SPS. The plasma levels of 177 selected proteins were analyzed.ResultsDifferences in the levels of 30 proteins were specific for SPS; 31 differences were specific for patients with both SPS and reduced mGFR; and 27 were specific for reduced mGFR. Eighteen of the differences specific for SPS concerned proteins described as promoting, or being associated with, atherosclerosis. Twelve of the differences specific for patients with both SPS and reduced mGFR and 10 of the differences specific for reduced mGFR also concerned proteins described as promoting, or being associated with, atherosclerosis. Almost all (82 of 88) of the concentration differences represented increased levels. For SPS, but not for reduced mGFR, a correlation between protein size and increase in level was observed, with smaller proteins being associated with higher levels.ConclusionThe high mortality in shrunken pore syndrome might be caused by the accumulation of atherosclerosis-promoting proteins in this condition.

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Section: Discussionmentioning

confidence: 69%

Shrunken Pore Syndrome Is Associated With Increased Levels of Atherosclerosis-Promoting Proteins

Almén

Björk

Nyman

et al. 2019

Kidney International Reports

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“…However, several studies have associated elevated OPG levels with cardiovascular events [34]. TNFRSF9 (downregulated) plays a key role in activating pro-inflammatory T-helper cells and is implicated in the progression of atherosclerosis [35].…”

Section: Discussionmentioning

confidence: 99%

Predictive value of targeted proteomics for coronary plaque morphology in patients with suspected coronary artery disease

et al. 2019

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BackgroundRisk stratification is crucial to improve tailored therapy in patients with suspected coronary artery disease (CAD). This study investigated the ability of targeted proteomics to predict presence of high-risk plaque or absence of coronary atherosclerosis in patients with suspected CAD, defined by coronary computed tomography angiography (CCTA).MethodsPatients with suspected CAD (n = 203) underwent CCTA. Plasma levels of 358 proteins were used to generate machine learning models for the presence of CCTA-defined high-risk plaques or complete absence of coronary atherosclerosis. Performance was tested against a clinical model containing generally available clinical characteristics and conventional biomarkers.FindingsA total of 196 patients with analyzable protein levels (n = 332) was included for analysis. A subset of 35 proteins was identified predicting the presence of high-risk plaques. The developed machine learning model had fair diagnostic performance with an area under the curve (AUC) of 0·79 ± 0·01, outperforming prediction with generally available clinical characteristics (AUC = 0·65 ± 0·04, p < 0·05). Conversely, a different subset of 34 proteins was predictive for the absence of CAD (AUC = 0·85 ± 0·05), again outperforming prediction with generally available characteristics (AUC = 0·70 ± 0·04, p < 0·05).InterpretationUsing machine learning models, trained on targeted proteomics, we defined two complementary protein signatures: one for identification of patients with high-risk plaques and one for identification of patients with absence of CAD. Both biomarker subsets were superior to generally available clinical characteristics and conventional biomarkers in predicting presence of high-risk plaque or absence of coronary atherosclerosis. These promising findings warrant external validation of the value of targeted proteomics to identify cardiovascular risk in outcome studies.FundThis study was supported by an unrestricted research grant from HeartFlow Inc. and partly supported by a European Research Area Network on Cardiovascular Diseases (ERA-CVD) grant (ERA CVD JTC2017, OPERATION). Funders had no influence on trial design, data evaluation, and interpretation.

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“…CD137 (4-1BB) is a tumor necrosis factor costimulatory receptor induced on a range of immune cells but also expressed at sites of human atherosclerotic plaque and genetically correlated with atherosclerotic disease (48,59). CD137 was first identified as an inducible T-cell gene expressed upon antigen activation (72), and now, CD137-agonistic regimens are being employed to generate durable-effector CD8 T-cell responses against certain cancers (40).…”

Section: Introductionmentioning

confidence: 99%

Direct CD137 costimulation of CD8 T cells promotes retention and innate-like function within nascent atherogenic foci

Ménoret

Nicholas

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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Effector CD8 T cells infiltrate atherosclerotic lesions and are correlated with cardiovascular events, but the mechanisms regulating their recruitment and retention are not well understood. CD137 (4–1BB) is a costimulatory receptor induced on immune cells and expressed at sites of human atherosclerotic plaque. Genetic variants associated with decreased CD137 expression correlate with carotid-intimal thickness and its deficiency in animal models attenuates atherosclerosis. These effects have been attributed in part to endothelial responses to low and disturbed flow (LDF), but CD137 also generates robust effector CD8 T cells as a costimulatory signal. Thus, we asked whether CD8 T cell-specific CD137 stimulation contributes to their infiltration, retention, and IFNγ production in early atherogenesis. We tested this through adoptive transfer of CD8 T cells into recipient C57BL/6J mice that were then antigen primed and CD137 costimulated. We analyzed atherogenic LDF vessels in normolipidemic and PCSK9-mediated hyperlipidemic models and utilized a digestion protocol that allowed for lesional T-cell characterization via flow cytometry and in vitro stimulation. We found that CD137 activation, specifically of effector CD8 T cells, triggers their intimal infiltration into LDF vessels and promotes a persistent innate-like proinflammatory program. Residence of CD137+ effector CD8 T cells further promoted infiltration of endogenous CD8 T cells with IFNγ-producing potential, whereas CD137-deficient CD8 T cells exhibited impaired vessel infiltration, minimal IFNγ production, and reduced infiltration of endogenous CD8 T cells. Our studies thus provide novel insight into how CD137 costimulation of effector T cells, independent of plaque-antigen recognition, instigates their retention and promotes innate-like responses from immune infiltrates within atherogenic foci. NEW & NOTEWORTHY Our studies identify CD137 costimulation as a stimulus for effector CD8 T-cell infiltration and persistence within atherogenic foci, regardless of atherosclerotic-antigen recognition. These costimulated effector cells, which are generated in pathological states such as viral infection and autoimmunity, have innate-like proinflammatory programs in circulation and within the atherosclerotic microenvironment, providing mechanistic context for clinical correlations of cardiovascular morbidity with increased CD8 T-cell infiltration and markers of activation in the absence of established antigen specificity. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/effector-cd8-t-cells-seed-atherogenic-foci/ .

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Human Genetic Evidence for Involvement of CD137 in Atherosclerosis

Cited by 9 publications

References 41 publications

Shrunken Pore Syndrome Is Associated With Increased Levels of Atherosclerosis-Promoting Proteins

Shrunken Pore Syndrome Is Associated With Increased Levels of Atherosclerosis-Promoting Proteins

Predictive value of targeted proteomics for coronary plaque morphology in patients with suspected coronary artery disease

Direct CD137 costimulation of CD8 T cells promotes retention and innate-like function within nascent atherogenic foci

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