Preventing the Increase in Lysophosphatidic Acids: A New Therapeutic Target in Pulmonary Hypertension?
Abstract
:1. Introduction
2. Results
2.1. Angiotensin-II Induced Hypertension (Ang-II HTN)
2.2. Chronic Heart Failure (CHF)
2.3. Pulmonary Hypertension (PH) Induced by Sugen/Hypoxia (SuHx)
2.4. Impact of LPA on Pulmonary Artery Smooth Muscle Cell (PA-SMC) Proliferation
2.5. Relationship between LPA Levels and Index of PH in Patients with Cardiac Dysfunction
3. Discussion
3.1. LPL, LPA and MAG Quantitation
3.2. CVD Models
3.3. LPA Signaling
4. Materials and Methods
4.1. Experimentation
4.1.1. Chemicals
4.1.2. Animals
4.2. LPL, LPA and MAG Quantitation
4.2.1. Blood Sampling and Processing
4.2.2. High Performance Liquid Chromatography (HPLC)
4.2.3. Tandem Mass Spectrometry (MS2)
4.3. Murine Models of Cardiovascular Diseases (CVD)
4.3.1. Angiotensin-II Induced Hypertension (HTN)
4.3.2. Chronic Heart Failure (CHF) Induced by Coronary Artery Ligation
4.3.3. Pulmonary Hypertension (PH) Induced by Sugen Hypoxia (SuHx)
4.4. Human PA-SMC Proliferation
4.5. Chronic Heart Failure Patients
4.6. Data and Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Analyte | Control Group (N = 8) | HTN Group (N = 8) | p-Value | Adjusted p-Value a |
---|---|---|---|---|
LPA(16:0) | 0.11 [0.11–0.12] | 0.15 [0.13–0.22] | 0.0229 | 0.241 |
LPA(18:0) b | 0.09 [0.08–0.10] | 0.11 [0.10–0.14] | 0.0832 | 0.341 |
LPA(18:1) | 0.09 [0.09–0.10] | 0.13 [0.10–0.14] | 0.0438 | 0.241 |
LPA(18:2) b | 1.78 [1.57–1.97] | 2.20 [1.56–2.46] | 0.163 | 0.398 |
LPA(20:4) b | 1.91 [1.50–2.13] | 2.56 [2.14–2.92] | 0.0308 | 0.241 |
LPA(22:6) b | 0.10 [0.08–0.11] | 0.14 [0.11–0.17] | 0.0931 | 0.341 |
LPC(16:0) | 16.7 [16.2–17.4] | 17.3 [15.0–18.0] | 0.568 | 0.781 |
LPC(16:1) b | 1.24 [1.10–1.40] | 1.58 [1.40–1.77] | 0.0438 | 0.241 |
LPC(18:0) b | 29.7 [27.3–32.9] | 30.4 [28.7–31.7] | 0.914 | 0.914 |
LPC(18:1) | 7.24 [6.36–7.53] | 7.22 [6.83–8.14] | 0.343 | 0.629 |
LPC(18:2) b | 31.5 [28.5–32.6] | 30.9 [28.2–32.0] | 0.749 | 0.867 |
LPC(20:4) b | 11.1 [10.3–12.1] | 12.6 [11.6–13.7] | 0.148 | 0.398 |
LPC(22:6) b | 0.34 [0.31–0.43] | 0.43 [0.38–0.46] | 0.269 | 0.538 |
LPE(16:0) | 0.54 [0.47–0.61] | 0.62 [0.58–0.68] | 0.118 | 0.371 |
LPE(18:0) b | 0.80 [0.76–0.93] | 0.95 [0.89–1.00] | 0.205 | 0.451 |
LPE(18:1) b | 0.22 [0.21–0.27] | 0.25 [0.22–0.27] | 0.376 | 0.636 |
LPE(18:2) b | 0.45 [0.44–0.52] | 0.46 [0.41–0.49] | 0.439 | 0.690 |
LPE(20:4) b | 0.16 [0.15–0.17] | 0.17 [0.16–0.20] | 0.836 | 0.876 |
LPE(22:6) b | 0.11 [0.09–0.12] | 0.12 [0.10–0.15] | 0.612 | 0.792 |
MAG(18:1) | 0.13 [0.10–0.16] | 0.12 [0.11–0.15] | 0.805 | 0.876 |
MAG(18:2) b | 0.67 [0.57–1.00] | 0.64 [0.58–0.79] | 0.673 | 0.823 |
MAG(20:4) b | 0.02 [0.02–0.03] | 0.02 [0.01–0.02] | 0.508 | 0.745 |
Analyte | Control Group (N = 8) | CHF Group (N = 9) | p-Value | Adjusted p-Value a |
---|---|---|---|---|
LPA(16:0) | 0.058 [0.046–0.060] | 0.082 [0.056–0.103] | 0.025 | 0.186 |
LPA(18:0) b | 0.050 [0.048–0.057] | 0.070 [0.065–0.080] | 0.336 | 0.615 |
LPA(18:1) | 0.069 [0.063–0.076] | 0.067 [0.054–0.075] | 0.757 | 0.779 |
LPA(18:2) b | 0.87 [0.77–0.95] | 1.00 [0.88–1.06] | 0.193 | 0.499 |
LPA(20:4) b | 1.24 [1.04–1.31] | 1.21 [1.14–1.56] | 0.204 | 0.499 |
LPA(22:6) b | 0.066 [0.062–0.070] | 0.068 [0.061–0.084] | 0.447 | 0.615 |
LPC(16:0) | 13.0 [11.3–14.2] | 12.3 [11.1–13.2] | 0.302 | 0.615 |
LPC(16:1) b | 1.06 [0.98–1.37] | 0.93 [0.71–1.60] | 0.750 | 0.779 |
LPC(18:0) b | 19.4 [15.7–20.5] | 18.7 [17.1–21.4] | 0.608 | 0.743 |
LPC(18:1) | 5.02 [4.61–5.64] | 3.97 [3.3–4.48] | 0.016 | 0.186 |
LPC(18:2) b | 19.7 [18.7–21.6] | 19.4 [17.1–20.5] | 0.430 | 0.615 |
LPC(20:4) b | 8.97 [8.27–10.63] | 8.4 [8.16–8.81] | 0.350 | 0.615 |
LPC(22:6) b | 0.386 [0.331–0.393] | 0.325 [0.274–0.362] | 0.196 | 0.499 |
LPE(16:0) | 0.55 [0.52–0.58] | 0.70 [0.61–0.72] | 0.017 | 0.186 |
LPE(18:0) b | 0.74 [0.63–0.79] | 0.82 [0.78–0.88] | 0.046 | 0.250 |
LPE(18:1) b | 0.25 [0.23–0.27] | 0.27 [0.25–0.30] | 0.425 | 0.615 |
LPE(18:2) b | 0.38 [0.37–0.42] | 0.44 [0.37–0.48] | 0.383 | 0.615 |
LPE(20:4) b | 0.158 [0.143–0.169] | 0.168 [0.167–0.201] | 0.089 | 0.390 |
LPE(22:6) b | 0.12 [0.11–0.14] | 0.14 [0.12–0.15] | 0.478 | 0.619 |
MAG(18:1) | 0.07 [0.06–0.09] | 0.11 [0.10–0.12] | 0.126 | 0.462 |
MAG(18:2) b | 0.18 [0.15–0.21] | 0.17 [0.11–0.26] | 0.756 | 0.779 |
MAG(20:4) b | 0.0061 [0.0049–0.0084] | 0.0068 [0.0045–0.0094] | 0.779 | 0.779 |
Analyte | Control Group (N = 10) | PH Group (N = 7) | p-Value | Adjusted p-Value a |
---|---|---|---|---|
LPA(16:0) | 0.091 [0.080–0.12] | 0.21 [0.19–0.26] | <0.001 | 0.003 |
LPA(18:0) b | 0.13 [0.11–0.17] | 0.19 [0.17–0.25] | 0.080 | 0.219 |
LPA(18:1) | 0.062 [0.056–0.085] | 0.156 [0.125–0.182] | <0.001 | 0.001 |
LPA(18:2) b | 0.99 [0.80–1.29] | 2.31 [2.03–4.00] | <0.001 | 0.001 |
LPA(20:4) b | 1.22 [1.05–1.51] | 2.18 [1.99–2.76] | <0.001 | 0.004 |
LPA(22:6) b | 0.064 [0.057–0.082] | 0.137 [0.119–0.160] | <0.001 | <0.001 |
LPC(16:0) | 16.8 [16.0–17.3] | 16.7 [14.9–17.2] | 0.357 | 0.604 |
LPC(16:1) b | 1.96 [1.625–2.07] | 1.99 [1.585–2.86] | 0.348 | 0.604 |
LPC(18:0) b | 32.8 [31.3–35.9] | 33.7 [30.7–36.0] | 0.749 | 0.827 |
LPC(18:1) | 7.01 [6.66–7.32] | 6.80 [6.11–7.31] | 0.485 | 0.686 |
LPC(18:2) b | 28.7 [26.3–30.2] | 28.1 [26.8–30.0] | 0.669 | 0.827 |
LPC(20:4) b | 11.1 [10.3–11.8] | 9.3 [7.6–10.4] | 0.231 | 0.462 |
LPC(22:6) b | 0.36 [0.32–0.39] | 0.36 [0.33–0.39] | 0.693 | 0.827 |
LPE(16:0) | 0.78 [0.73–0.79] | 0.81 [0.80–1.03] | 0.015 | 0.056 |
LPE(18:0) b | 1.14 [1.05–1.28] | 1.39 [1.23–1.48] | 0.053 | 0.168 |
LPE(18:1) b | 0.29 [0.27–0.34] | 0.38 [0.335–0.42] | 0.149 | 0.328 |
LPE(18:2) b | 0.53 [0.47–0.59] | 0.62 [0.53–0.66] | 0.457 | 0.686 |
LPE(20:4) b | 0.23 [0.21–0.25] | 0.22 [0.18–0.24] | 0.131 | 0.320 |
LPE(22:6) b | 0.158 [0.143–0.167] | 0.176 [0.146–0.179] | 0.752 | 0.827 |
MAG(18:1) | 0.095 [0.066–0.156] | 0.089 [0.058–0.113] | 0.499 | 0.686 |
MAG(18:2) b | 0.70 [0.40–1.10] | 0.60 [0.41–0.98] | 0.860 | 0.860 |
MAG(20:4) b | 0.014 [0.011–0.018] | 0.015 [0.006–0.023] | 0.806 | 0.844 |
Analyte | Mass Transition | MS Parameters | Adduct | Retention Time (min) | |||
---|---|---|---|---|---|---|---|
m/z (MS1) | m/z (MS2) | DP (V) | CE (eV) | CXP (V) | |||
LPA(16:0) | 409.5 | 152.9 | −50 | −40 | −10 | [M–H]− | 6.8 |
LPA(17:1) a | 421.1 | 152.9 | −50 | −40 | −10 | [M–H]− | 6.5 |
LPA(18:0) b | 437.3 | 152.9 | −50 | −40 | −10 | [M–H]− | 7.7 |
LPA(18:1) | 435.2 | 152.9 | −50 | −40 | −10 | [M–H]− | 7.0 |
LPA(18:2) b | 433.2 | 152.9 | −50 | −40 | −10 | [M–H]− | 6.3 |
LPA(20:4) b | 457.2 | 152.9 | −50 | −40 | −10 | [M–H]− | 6.3 |
LPA(22:6) b | 481.2 | 152.9 | −50 | −40 | −10 | [M–H]− | 6.3 |
LPC(16:0) | 480.6 | 255.4 | −80 | −40 | −10 | [M–CH3]− | 7.2 |
LPC(16:1) b | 478.6 | 253.4 | −100 | −40 | −10 | [M–CH3]− | 6.3 |
LPC(17:1) a | 492.3 | 267.3 | −80 | −40 | −10 | [M–CH3]− | 6.8 |
LPC(18:0) b | 508.4 | 283.5 | −100 | −40 | −10 | [M–CH3]− | 8.1 |
LPC(18:1) | 506.4 | 281.5 | −80 | −40 | −10 | [M–CH3]− | 7.4 |
LPC(18:2) b | 504.4 | 279.5 | −100 | −40 | −10 | [M–CH3]− | 6.7 |
LPC(20:4) b | 528.4 | 303.4 | −100 | −40 | −10 | [M–CH3]− | 6.7 |
LPC(22:6) b | 552.4 | 327.4 | −100 | −40 | −10 | [M–CH3]− | 6.6 |
LPE(16:0) | 452.4 | 196.0 | −50 | −40 | −10 | [M–H]− | 7.2 |
LPE(17:1) | 464.2 | 196.0 | −80 | −40 | −10 | [M–H]− | 6.9 |
LPE(18:0) b | 480.3 | 196.0 | −50 | −40 | −10 | [M–H]− | 8.1 |
LPE(18:1) b | 478.3 | 196.0 | −50 | −40 | −10 | [M–H]− | 7.4 |
LPE(18:2) b | 476.3 | 196.0 | −50 | −40 | −10 | [M–H]− | 6.8 |
LPE(20:4) b | 500.6 | 196.0 | −50 | −40 | −10 | [M–H]− | 6.7 |
LPE(22:6) b | 524.3 | 196.0 | −50 | −40 | −10 | [M–H]− | 6.7 |
MAG(18:1) | 357.2 | 265.0 | 50 | 17 | 16 | [M+H]+ | 8.0 |
MAG(18:2) b | 355.2 | 263.0 | 50 | 17 | 16 | [M+H]+ | 7.5 |
MAG(20:4) b | 379.3 | 287.1 | 50 | 17 | 16 | [M+H]+ | 7.4 |
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Duflot, T.; Tu, L.; Leuillier, M.; Messaoudi, H.; Groussard, D.; Feugray, G.; Azhar, S.; Thuillet, R.; Bauer, F.; Humbert, M.; et al. Preventing the Increase in Lysophosphatidic Acids: A New Therapeutic Target in Pulmonary Hypertension? Metabolites 2021, 11, 784. https://doi.org/10.3390/metabo11110784
Duflot T, Tu L, Leuillier M, Messaoudi H, Groussard D, Feugray G, Azhar S, Thuillet R, Bauer F, Humbert M, et al. Preventing the Increase in Lysophosphatidic Acids: A New Therapeutic Target in Pulmonary Hypertension? Metabolites. 2021; 11(11):784. https://doi.org/10.3390/metabo11110784
Chicago/Turabian StyleDuflot, Thomas, Ly Tu, Matthieu Leuillier, Hind Messaoudi, Déborah Groussard, Guillaume Feugray, Saïda Azhar, Raphaël Thuillet, Fabrice Bauer, Marc Humbert, and et al. 2021. "Preventing the Increase in Lysophosphatidic Acids: A New Therapeutic Target in Pulmonary Hypertension?" Metabolites 11, no. 11: 784. https://doi.org/10.3390/metabo11110784