Upregulation of Myocardial and Vascular Phosphodiesterase 9A in A Model of Atherosclerotic Cardiovascular Disease
Abstract
:1. Introduction
2. Results
2.1. Atherogenic Diet Induces Cardiac Dysfunction
2.2. Increased Left Ventricle Mass and Bodyweight in HC Animals
2.3. Atherogenic Diet Elevates Serum Lipid Parameters
2.4. Atherogenic Diet and Endothelial Dysfunction with Increased Aortic PDE9A Expression
2.5. Plaque Coverage and Interstitial Fibrosis in HC Animals
2.6. Atherogenic Diet Correlates with the Upregulation of Myocardial PDE9A and PKG1
3. Discussion
3.1. Cardiac Dysfunction
3.2. Dyslipidemia and Endothelial Dysfunction
3.3. Upregulation of Cardiac PDE9A in Correlation with Cardiac Dysfunction
3.4. Translational Aspects and Future Directions
4. Materials and Methods
4.1. Animal Model
4.2. Chemicals
4.3. Study Design
4.4. Echocardiographic Studies
4.5. Strain (Speckle Tracking) Analyses
4.6. Analysis of Serum Parameters
4.7. Morphometry
4.8. Functional Vascular Assays
4.9. Histology
4.10. Western Blot
4.11. cGMP Assay
4.12. Statistical Analyses
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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2D and M-Mode | Baseline (n = 9) Start | Control (n = 9) Endpoint | HC (n = 9) Endpoint | p Value (HC vs. Control) |
LA area (cm2) | 0.789 ± 0.054 | 0.833 ± 0.029 | 1.633 ± 0.065 **** | <0.0001 |
IVSd (mm) | 2.153 ± 0.074 | 2.27 ± 0.139 | 2.882 ± 0.176 * | 0.0149 |
LV mass (g) | 4.057 ± 0.292 | 4.651 ± 0.433 | 8.035 ± 0.655 *** | 0.0005 |
RWT (%) | 0.260 ± 0.020 | 0.283 ± 0.017 | 0.362 ± 0.018 ** | 0.0050 |
LV FS (%) | 32.1 ± 0.706 | 30.78 ± 0.434 | 28.44 ± 0.669 ** | 0.0099 |
LV EF (%) | 63.9 ± 0.994 | 62.22 ± 0.619 | 58.33 ± 0.898 ** | 0.0026 |
MAPSE (mm) | 5.263 ± 0.209 | 5.488 ± 0.093 | 5.661 ± 0.254 | 0.5147 |
LVOT Parameters | Baseline | Control | HC | p Value |
Vmax (m/s) | 0.884 ± 0.016 | 0.923 ± 0.018 | 1.204 ± 0.021 **** | <0.0001 |
Vmean (m/s) | 0.542 ± 0.012 | 0.601 ± 0.018 | 0.701 ± 0.027 ** | 0.0076 |
maxPG (mmHg) | 3.141 ± 0.117 | 3.453 ± 0.139 | 5.832 ± 0.199 **** | <0.0001 |
meanPG (mmHg) | 1.478 ± 0.054 | 1.747 ± 0.104 | 2.637 ± 0.172 *** | 0.0004 |
Doppler and TVI | Baseline (n = 9) Start | Control (n = 9) Endpoint | HC (n = 9) Endpoint | p Value (HC vs. Control) |
MV E vel (m/s) | 0.707 ± 0.036 | 0.630 ± 0.022 | 0.698 ± 0.047 | 0.2049 |
MV A vel (m/s) | 0.399 ± 0.023 | 0.391 ± 0.012 | 0.653 ± 0.042 **** | <0.0001 |
E/A ratio | 1.836 ± 0.139 | 1.624 ± 0.068 | 1.069 ± 0.039 **** | <0.0001 |
DecT (ms) | 58.30 ± 2.864 | 55.44 ± 2.001 | 71.22 ± 2.666 *** | 0.0002 |
Sept e’/a’ ratio | 1.538 ± 0.078 | 1.233 ± 0.060 | 0.935 ± 0.054 ** | 0.0020 |
E/e’ ratio | 8.311 ± 0.165 | 8.002 ± 0.164 | 13.20 ± 1.091 *** | 0.0002 |
IVRT (ms) | 34.10 ± 1.690 | 30.78 ± 1.188 | 56.56 ± 2.588 **** | <0.0001 |
Tei-index (MPI) | 0.560 ± 0.017 | 0.528 ± 0.013 | 0.8385 ± 0.049 **** | <0.0001 |
Strain Data | Baseline | Control | HC | p Value |
GLS | −22.50 ± 0.806 | −21.34 ± 0.664 | −16.07 ± 1.029 *** | 0.0007 |
Parameter | Control (n = 9) | HC (n = 9) Endpoint |
---|---|---|
Bodyweight (g) | 3064 ± 87 | 4153 ± 86 *** |
Heart weight | 7.795 ± 0.418 | 12.25 ± 0.535 *** |
Heart weight to BW ratio | 0.00253 ± 0.0003 | 0.00294 ± 0.0002 |
Left ventricle mass (g) | 6.22 ± 0.337 | 10.13 ± 0.534 *** |
LV mass to tibial length | 0.605 ± 0.046 | 0.828 ± 0.038 ** |
LV mass to BW ratio | 0.00087 ± 0.0003 | 0.0008 ± 0.0002 |
Lung wet to dry ratio | 5.254 ± 0.147 | 5.118 ± 0.094 |
Kidney wet to dry ratio | 3.421 ± 0.058 | 3.281 ± 0.191 |
Serum Parameter | Baseline (n = 9) Start | Control (n = 9) Endpoint | HC (n = 9) Endpoint | p Value (HC vs. Control) |
---|---|---|---|---|
Total chol. (mmol/L) | 3.440 ± 0.199 | 1.753 ± 0.0187 | 32.360 ± 2.164 **** | <0.0001 |
LDLc (mmol/L) | 2.759 ± 0.317 | 0.725 ± 0.312 | 32.030 ± 1.813 **** | <0.0001 |
ApoB (mmol/L) | 0.057 ± 0.008 | 0.026 ± 0.005 | 0.154 ± 0.006 **** | <0.0001 |
HDLc (mmol/L) | 1.188 ± 0.212 | 0.963 ± 0.092 | 6.428 ± 0.600 **** | <0.0001 |
ApoA (mmol/L) | 0.112 ± 0.024 | 0.149 ± 0.011 | 0.034 ± 0.007 **** | <0.0001 |
Atherogenic index | 2.457 ± 0.170 | 1.986 ± 0.391 | 5.499 ± 0.458 *** | 0.0001 |
ApoB to ApoA ratio | 0.385 ± 0.046 | 0.188 ± 0.041 | 3.691 ± 0.492 **** | <0.0001 |
Triglyceride (mmol/L) | 0.410 ± 0.066 | 1.139 ± 0.136 | 1.001 ± 0.225 | 0.6959 |
AST (GOT) (U/L) | 25.000 ± 5.177 | 22.710 ± 6.781 | 33.47 ± 3.016 | 0.1056 |
ALT (GPT) (U/L) | 50.830 ± 8.284 | 64.140 ± 19.660 | 57.730 ± 5.479 | 0.6813 |
Creatinine (μmol/L) | 83.000 ± 6.033 | 71.430 ± 12.040 | 116.100 ± 5.984 ** | 0.0013 |
CK-MB (U/L) | 1077.0 ± 384.7 | 1154.0 ± 276.9 | 785.6 ± 126.1 | 0.1754 |
Insulin (µIU/mL) | 17.63 ± 0.41 | 23.70 ± 2.46 | 49.38 ± 6.70 ** | 0.0089 |
Glucose (mmol/L) | 4.917 ± 0.202 | 7.100 ± 0.245 | 6.918 ± 0.278 | 0.7178 |
CRP (mg/L) | 0.251 ± 0.075 | 0.079 ± 0.070 | 0.325 ± 0.073 * | 0.0359 |
Troponin T (ng/L) | 5.528 ± 1.010 | 7.438 ± 1.199 | 20.21 ± 2.778 ** | 0.0092 |
Parameter | Control | HC |
---|---|---|
Emax | 93.67 ± 2.66 | 50.9 ± 9.48 ** |
logEC50 | −8.62 ± 0.36 | −7.59 ± 0.16 * |
n | 0.91 ± 0.19 | 1 ± 0.11 |
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Priksz, D.; Bombicz, M.; Varga, B.; Kurucz, A.; Gesztelyi, R.; Balla, J.; Toth, A.; Papp, Z.; Szilvassy, Z.; Juhasz, B. Upregulation of Myocardial and Vascular Phosphodiesterase 9A in A Model of Atherosclerotic Cardiovascular Disease. Int. J. Mol. Sci. 2018, 19, 2882. https://doi.org/10.3390/ijms19102882
Priksz D, Bombicz M, Varga B, Kurucz A, Gesztelyi R, Balla J, Toth A, Papp Z, Szilvassy Z, Juhasz B. Upregulation of Myocardial and Vascular Phosphodiesterase 9A in A Model of Atherosclerotic Cardiovascular Disease. International Journal of Molecular Sciences. 2018; 19(10):2882. https://doi.org/10.3390/ijms19102882
Chicago/Turabian StylePriksz, Daniel, Mariann Bombicz, Balazs Varga, Andrea Kurucz, Rudolf Gesztelyi, Jozsef Balla, Attila Toth, Zoltan Papp, Zoltan Szilvassy, and Bela Juhasz. 2018. "Upregulation of Myocardial and Vascular Phosphodiesterase 9A in A Model of Atherosclerotic Cardiovascular Disease" International Journal of Molecular Sciences 19, no. 10: 2882. https://doi.org/10.3390/ijms19102882
APA StylePriksz, D., Bombicz, M., Varga, B., Kurucz, A., Gesztelyi, R., Balla, J., Toth, A., Papp, Z., Szilvassy, Z., & Juhasz, B. (2018). Upregulation of Myocardial and Vascular Phosphodiesterase 9A in A Model of Atherosclerotic Cardiovascular Disease. International Journal of Molecular Sciences, 19(10), 2882. https://doi.org/10.3390/ijms19102882