Clinical and Population Studies

Plasma Soluble Endoglin Levels Are Inversely Associated With the Severity of Coronary Atherosclerosis—Brief ReportHighlights

Emi Saita, Kotaro Miura, Norie Suzuki-Sugihara, Koutaro Miyata, Nobuhiro Ikemura, Reiko Ohmori, Yukinori Ikegami, Yoshimi Kishimoto, Kazuo Kondo, Yukihiko Momiyama
https://doi.org/10.1161/ATVBAHA.116.308494
Arteriosclerosis, Thrombosis, and Vascular Biology. 2017;37:49-52
Originally published October 27, 2016

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Abstract

Objective—Transforming growth factor-β inhibits migration and proliferation of endothelial and smooth muscle cells. Endoglin is a transmembrane receptor for transforming growth factor-β1 and transforming growth factor-β3. Endoglin is released into blood as a soluble form (soluble endoglin [sEng]), but plasma sEng levels in patients with coronary artery disease (CAD) have not been elucidated.

Approach and Results—We measured plasma sEng levels in 244 patients undergoing coronary angiography. The severity of coronary atherosclerosis was evaluated as the numbers of >50% stenotic vessels and segments. CAD was found in 147 patients, of whom 55 had 1-vessel, 42 had 2-vessel, and 50 had 3-vessel disease. Compared with 97 patients without CAD, 147 with CAD had lower sEng levels (median 4.04 versus 4.37 ng/mL; P<0.005). A stepwise decrease in sEng levels was found based on the number of stenotic vessels: 4.37 in CAD(−), 4.23 in 1-vessel, 4.13 in 2-vessel, and 3.74 ng/mL in 3-vessel disease (P<0.005). sEng levels inversely correlated with the number of stenotic segments (r=−0.25; P<0.001). In multivariate analysis, sEng was an independent factor for 3-vessel disease and CAD. Odds ratios for CAD and 3-vessel disease were 0.97 (95% confidence interval, 0.95–0.99; P<0.02) and 0.96 (95% confidence interval, 0.93–0.99; P<0.01) for a 0.1 ng/mL increase in sEng levels, respectively.

Conclusions—Plasma sEng levels were low in patients with CAD, especially 3-vessel disease, and were inversely associated with the severity of coronary atherosclerosis.

Introduction

Transforming growth factor-β (TGF-β) plays an important role in regulating the progression of atherosclerosis because of its inhibitory effect on migration and proliferation of endothelial cells, smooth muscle cells, and macrophages.1 In apolipoprotein E–deficient mice, TGF-β inhibition accelerated atherosclerosis.2 TGF-β is, thus, recognized to have a protective effect against atherosclerosis.

See accompanying editorial on page 10

Endoglin, also called TGF-β receptor III, is a transmembrane receptor for TGF-β1 and TGF-β3 that regulates TGF-β signaling.3 Inhibition of endoglin enhances TGF-β1 signaling to suppress the migration and growth of endothelial cells, thus suggesting its inhibitory effect on TGF-β1.4 Endoglin is highly expressed in endothelial cells of inflamed tissues, healing wounds, vascular injury, and angiogenesis.5,6 Endoglin expression was found to be upregulated in endothelial and smooth muscle cells of human aortic and coronary atherosclerotic plaques.7,8 Piao and Tokunaga9 also reported high expression of both endoglin and TGF-β1 in human atherosclerotic aortic tissues. Moreover, high expression of both endoglin and TGF-β1 was shown to correlate with increased plaque collagen and smooth muscle cell contents and plaque stability.10

Endoglin is released into circulation as a soluble form (soluble endoglin [sEng]) in various conditions related to endothelial injury and inflammation.3 Role of sEng in regulating TGF-β signaling is considered as a TGF-β antagonist.3 Increased sEng levels in blood and enhanced atherosclerosis with decreased endoglin expression were demonstrated in apolipoprotein E/low-density lipoprotein (LDL) receptor knockout mice fed by cholesterol-rich diet.11 Increased sEng levels may result in reduced TGF-β signaling, leading to enhanced atherosclerosis. However, blood sEng levels in patients with atherosclerotic diseases, such as coronary artery disease (CAD), remain controversial. One study reported blood sEng levels to be high in 26 patients with peripheral artery disease (PAD) but not in 29 patients with CAD,12 whereas another study showed sEng levels to be low in 36 CAD patients with 3-vessel disease.13 Therefore, our study was done to elucidate the association between plasma sEng levels and CAD in 244 patients undergoing elective coronary angiography, of whom 216 also had an ankle-brachial index test for screening of PAD.

Materials and Methods

Materials and Methods are available in the online-only Data Supplement.

Results

Of the 244 study patients, CAD was found in 147 patients, of whom 55 had 1-vessel, 42 had 2-vessel, and 50 had 3-vessel disease. Compared with 97 patients without CAD, 147 with CAD had lower sEng levels (median: 4.04 versus 4.37 ng/mL; P<0.005; Table). A stepwise decrease in sEng levels was found depending on the number of >50% stenotic coronary vessels: 4.37 in CAD(−), 4.23 in 1-vessel, 4.13 in 2-vessel, and 3.74 ng/mL in 3-vessel disease (P<0.005; Figure 1). Moreover, sEng levels inversely correlated with the number of >50% stenotic coronary segments and the severity score of stenosis (rs=−0.25 and rs=−0.22; P<0.001; Figure 2).

View this table:
Table.

Clinical Characteristics and Plasma sEng Levels

Figure 1.
Figure 1.

Plasma soluble endoglin (sEng) levels in patients with and without coronary artery disease (CAD). A stepwise decrease in sEng levels was found depending on the number of >50% stenotic coronary vessels (P<0.005 by the Kruskal–Wallis test). Especially, sEng levels in 3-vessel disease (VD) were lower than those in CAD(−) (P<0.05 by the Steel–Dwass test). The central line represents the median, the boxes span from the 25th to 75th percentiles, and the error bars extend from the 10th to 90th percentiles.

Figure 2.
Figure 2.

Inverse correlation between plasma soluble endoglin (sEng) levels and the severity score of coronary stenosis. Plasma sEng levels significantly but weakly correlated inversely with the severity score of coronary stenosis (rs=−0.22; P<0.001).

Of the 216 patients (133 with CAD and 83 without CAD) who also had an ankle-brachial index test, 20 were found to have PAD. Even after excluding 20 patients with PAD, sEng levels were lower in patients with CAD than those without CAD (P<0.01). Notably, all 20 patients with PAD also had CAD and more often had 3-vessel disease than 113 CAD patients without PAD (65% versus 27%; P<0.01). However, no significant difference was found in sEng levels between CAD patients with and without PAD (3.18 versus 4.07 ng/mL; P=not significant).

To elucidate independent associations between sEng and CAD, variables (age, hypertension, hyperlipidemia, statin use, diabetes mellitus, smoking, and sEng levels) were entered into a multiple logistic regression model. The sEng levels were found to be an independent factor for 3-vessel disease and CAD. Odds ratios for CAD and 3-vessel disease were 0.97 (95% confidence interval, 0.95–0.99; P<0.02) and 0.96 (95% confidence interval, 0.93–0.99; P<0.01) for a 0.1 ng/mL increase in sEng levels, respectively.

Discussion

The present study reported that plasma sEng levels were low in patients with stable CAD, especially in 3-vessel disease, and that sEng levels inversely correlated with the severity of coronary atherosclerosis, defined as the numbers of stenotic vessels and segments. However, sEng levels in CAD patients with PAD were not higher than those in CAD patients without PAD.

Although sEng inhibits TGF-β function, leading to enhanced atherogenesis,3 sEng levels in patients with atherosclerotic diseases or risk factors have not been clarified. In apolipoprotein E/LDL receptor knockout mice, hyperlipidemia was shown to cause increased blood sEng level and enhanced atherosclerosis with decreased endoglin expression,11 and atorvastatin treatment resulted in LDL cholesterol reduction and decreased sEng levels and decreased atherosclerotic lesions with increased endoglin expression.14 In humans, Blaha et al15 demonstrated serum sEng levels to be high in 11 patients with familial hypercholesterolemia and to decrease after extracorporeal LDL cholesterol elimination. Blázquez-Medela et al16 measured plasma sEng levels in 64 diabetic patients, 159 hypertensive patients, and 65 healthy controls. They reported sEng levels to be higher in diabetic patients with retinopathy, in those with high probability of 10-year cardiovascular risk, and in those with hypertension and ≥3 damaged organs. However, there was no significant difference in sEng levels among diabetic patients without hypertension, those with hypertension, hypertensive patients, and controls (5.02±0.98, 4.88±1.20, 4.39±1.04, and 5.21±1.10 ng/mL). It remains unclear whether or not patients with atherosclerotic risk factors may have high sEng levels.

About blood sEng levels in patients with atherosclerotic disease, Blann et al12 measured serum sEng levels in 29 patients with CAD, 26 with PAD, and 26 controls. They reported sEng levels to be higher in PAD patients but not in CAD patients than in controls. Cruz-Gonzalez et al17 investigated sEng levels in 183 patients with acute myocardial infarction. They showed sEng levels in acute myocardial infarction patients to be low and to decrease further after acute myocardial infarction. Li et al13 investigated serum levels of sEng, TGF-β, and endoglin/TGF-β complexes in 36 CAD patients with 3-vessel disease, 30 with chest pain, positive exercise test but normal coronary angiogram, and 31 controls. Compared with controls, sEng levels were lower in CAD patients but higher in patients with chest pain but normal angiogram. Notably, levels of endoglin/TGF-β complexes were higher in CAD patients, suggesting that increased formation of endoglin/TGF-β complexes may be responsible for lower sEng levels in CAD patients. They speculated that sEng levels increased in early stage of atherosclerosis because of endothelial damage and decreased in later stage because of increased formation of endoglin/TGF-β1 complexes. Similarly, our study showed sEng levels to be lower in 147 patients with CAD than in 97 without CAD and to be lowest in 50 patients with 3-vessel disease. Moreover, we demonstrated that sEng levels inversely correlated with the severity of coronary atherosclerosis. However, we could not measure levels of endoglin/TGF-β complexes. In apolipoprotein E/LDL receptor knockout mice, hyperlipidemia caused increased sEng levels and enhanced atherosclerosis with decreased endoglin expression.11 In human coronary atherosclerotic plaques, increased endoglin expression was reported.7,8 Therefore, we also speculate that patients with CAD may have decreased blood sEng levels and increased endoglin expression of coronary atherosclerotic plaques.

In our study, 20 of 133 patients with CAD (15%) were found to have PAD by ankle-brachial index test. This prevalence of PAD was similar to that reported by Lee et al18 (385 of 2424 patients with CAD [16%]). Blann et al12 reported sEng levels to be high in 26 patients with PAD. However, in our study, sEng levels were not higher but rather lower in CAD patients with PAD than in those without PAD, possibly because of higher prevalence of 3-vessel disease in patients with PAD. To elucidate sEng levels in patients with PAD, a further study in a large number of PAD patients is needed. Even after excluding 20 patients with PAD, our study showed sEng levels to be significantly lower in patients with CAD than in those without CAD.

Luque at al19 investigated endoglin expression in carotid, coronary, and cerebral arteries and showed high endoglin expression in atherosclerotic lesions. However, cerebral artery had less endoglin expression despite atherosclerosis, suggesting differences in separate vascular beds. Blann et al12 also reported high sEng levels in PAD patients but not in CAD patients. Hence, the levels of endoglin expression and the amount of sEng released into circulation may vary in different vascular beds. As in Figures 1 and 2, there was some overlap in sEng levels of patients with and without CAD, and correlations between sEng levels and coronary atherosclerosis were significant but weak (rs=−0.25 and −0.22; P<0.001). Therefore, plasma sEng levels may reflect not only coronary atherosclerosis but also atherosclerosis in other vascular beds.

Our study has several limitations. In our study, angiography was used to evaluate coronary atherosclerosis. However, angiography cannot visualize plaques and only shows lumen characteristics. Moreover, we measured only sEng levels and could not measure levels of endoglin/TGF-β complexes, because of no commercially available kits for the measurement of endoglin/TGF-β complexes now. This is one of major study limitations.

Thus, plasma sEng levels were low in patients with CAD, especially in 3-vessel disease, and were inversely associated with the severity of coronary atherosclerosis.

Sources of Funding

Financial funding of this study was provided in part by Daiichi Sankyo, Co, and Pfizer Japan, Inc.

Disclosures

None.

Footnotes

  • The study sponsors had no role in the design, analysis, and interpretation of the study.

  • The online-only Data Supplement is available with this article at http://atvb.ahajournals.org/lookup/suppl/doi:10.1161/ATVBAHA.116.308494/-/DC1.

  • Nonstandard Abbreviations and Acronyms
    CAD
    coronary artery disease
    LDL
    low-density lipoprotein
    PAD
    peripheral artery disease
    sEng
    soluble endoglin
    TGF-β
    transforming growth factor-β

  • Received June 26, 2016.
  • Accepted October 6, 2016.

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Highlights

  • Plasma soluble endoglin levels were low in patients with stable coronary artery disease, especially in 3-vessel disease.

  • Plasma soluble endoglin levels significantly but weakly correlated inversely with the severity of coronary atherosclerosis, defined as the numbers of stenotic vessels and segments.

  • Although 15% of patients with coronary artery disease had peripheral artery disease, soluble endoglin levels in coronary artery disease patients with peripheral artery disease were not higher than those in coronary artery disease patients without peripheral artery disease.

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  • Plasma Soluble Endoglin Levels Are Inversely Associated With the Severity of Coronary Atherosclerosis—Brief ReportHighlights
    Emi Saita, Kotaro Miura, Norie Suzuki-Sugihara, Koutaro Miyata, Nobuhiro Ikemura, Reiko Ohmori, Yukinori Ikegami, Yoshimi Kishimoto, Kazuo Kondo and Yukihiko Momiyama
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2017;37:49-52, originally published October 27, 2016
    https://doi.org/10.1161/ATVBAHA.116.308494
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