Association of the Serpine1 with the Obesity Paradox in Ischemic Heart Failure
Abstract
Background: Extreme obesity pathology is with a risk factor for heart failure (HF), whereas the obesity paradox in HF shows that obese subjects had a good prognosis. The mechanism underlying the obesity paradox in HF prognosis is unclear till now. We aimed to provide evidence for the molecular mechanisms of the obesity paradox in HF.
Methods: Differentially expressed genes (DEGs) in ischemic HF samples were identified in the GSE57338 and GSE5406 datasets. Weighted gene co-expression network analysis (WGCNA) modules and a protein-protein interaction network (PPI) were constructed. HF-associated DEGs and pathways were screened in the Comparative Toxicogenomics Database (CTD). The expression of hub genes in adipose tissues from obese patients and LV samples from HF patients were validated in microarray datasets.
Results: Three HF-associated WGCNA modules were identified and DEGs were associated with the ‘hsa04115: p53 signaling pathway’. SERPINE1 was the only common gene between DEGs and HF-associated genes in the CTD database. The SERPINE1 gene was downregulated in the white adipose tissues compared with brown adipose tissues (P = 3.90e-03) and was upregulated in the omental adipose tissues from obese patients compared with lean subjects (P = 3.85e-02).
Conclusion: The downregulation of SERPINE1 expression might be responsible for the obesity paradox in HF via interacting with ESR1.
1. Zhang H, Pan B, Wu P, Parajuli N, Rekhter MD, Goldberg AL, Wang X (2019). PDE1 inhibition facilitates proteasomal degradation of misfolded proteins and protects against cardiac proteinopathy. Sci Adv, 5(5): eaaw5870.
2. Najafi F, Dobson AJ, Hobbs M, Jamrozik K (2014). Temporal trends in the frequency and longer-term outcome of heart failure complicating myocardial infarction. Eur J Heart Fail, 9(9): 879-885.
3. Dharmarajan K, Hsieh AF, Kulkarni VT, et al (2015). Trajectories of risk after hospitalization for heart failure, acute myocardial infarction, or pneumonia: retrospective cohort study. BMJ, 350(feb05 19):h411.
4. Sartini S, Frizzi J, Borselli M, et al (2016). Which method is best for an early accurate diagnosis of acute heart failure? Comparison between lung ultrasound, chest X-ray and NT pro-BNP performance: a prospective study. Intern Emerg Med, 12(6):861-869.
5. Magnussen C, Blankenberg S (2018). Biomarkers for heart failure: small molecules with high clinical relevance. J Intern Med, 283(6):530-543.
6. Linssen GCM, Jaarsma T, Hillege HL, Voors AA, Veldhuisen DJV (2018). A comparison of the prognostic value of BNP versus NT-proBNP after hospitalisation for heart failure. Neth Heart J, 26(10):486-492.
7. Berezin AE, Kremzer AA, Martovitskaya YV, Berezina TA, Samura TA (2015). The utility of biomarker risk prediction score in patients with chronic heart failure. Int J Clin Exp Med,8(10):18255-64.
8. Ahmad FS, Ning H, Rich J, Lloyd-Jones D, Wilkins J (2016). Hypertension, obesity, diabetes, and heart failure-free survival: the cardiovascular lifetime risk pooling project. JACC Heart Fail, 4(12):911-919.
9. Lavie CJ, Sharma A, Alpert MA, et al (2016). Update on Obesity and Obesity Paradox in Heart Failure. Prog Cardiovasc Dis, 58(4):393-400.
10. Chrysant G S (2018). Obesity is bad regardless of the obesity paradox for hypertension and heart disease. J Clin Hypertens (Greenwich), 20(5):842-846.
11. Abhishek S, Lavie CJ, Borer JS, et al (2015). Meta-analysis of the relation of body mass index to all-cause and cardiovascular mortality and hospitalization in patients with chronic heart failure. Am J Cardiol, 115(10):1428-1434.
12. Elagizi A, Kachur S, Lavie C, et al (2018). An Overview and Update on Obesity and the Obesity Paradox in Cardiovascular Diseases. Prog Cardiovasc Dis, 61(2):142-150.
13. Patricia LL, Maria Luisa M, Marian Angeles Z, Jose Alfredo M (2013). SERPINE1, PAI-1 protein coding gene, methylation levels and epigenetic relationships with adiposity changes in obese subjects with metabolic syndrome features under dietary restriction. J Clin Biochem Nutr, 53(3):139-144.
14. Kaur P, Reis MD, Couchman GR, Forjuoh SN, Greene JF, Asea A (2010). SERPINE 1 Links Obesity and Diabetes: A Pilot Study. J Proteomics Bioinform, 3(6):191-99.
15. Langfelder P, Horvath S (2008). WGCNA: an R package for weighted correlation network analysis. BMC bioinformatics, 9(1):559.
16. Cao J, Zhang S (2014). Bayesian extension of the hypergeometric test for functional enrichment analysis. Biometrics, 70(1):84-94.
17. Matsushita M, Shirakabe A, Hata N, et al (2016). Association between the body mass index and the clinical findings in patients with acute heart failure: evaluation of the obesity paradox in patients with severely decompensated acute heart failure. Heart Vessels, 32(5): 600-608.
18. Alessi MC, Peiretti F, Morange P, Henry M, Nalbone G, Juhan-Vague I (1997). Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Diabetes, 46(5):860-867.
19. Juhan-Vague I, Alessi MC, Vague P (1991). Increased plasma plasminogen activator inhibitor 1 levels. A possible link between insulin resistance and atherothrombosis. Diabetologia, 34(7):457-462.
20. Andreas F, Ralph DA, Tracy RP, Haffner SM (2002). Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes, 51(4):1131-7.
21. Thomas K, Anatoly S, Ulrike R, Kurt J (2003). Hypoxia-inducible factor-1 and hypoxia response elements mediate the induction of plasminogen activator inhibitor-1 gene expression by insulin in primary rat hepatocytes. Blood, 101(3):907-914.
22. Tsai CH, Lee SS, Huang FM, Yu CC, Yang SF, Chang YC (2015). The modulation of hypoxia-inducible factor-1α/plasminogen activator inhibitor-1 axis in human gingival fibroblasts stimulated with cyclosporine A. J Formos Med Assoc, 114(1):58-63.
23. Kaikita K, Fogo AB, Ma L, Schoenhard JA, Brown NJ, Vaughan DE (2001). Plasminogen activator inhibitor-1 deficiency prevents hypertension and vascular fibrosis in response to long-term nitric oxide synthase inhibition. Circulation, 104(7):839-844.
24. Jung RG, Motazedian P, Ramirez FD, et al (2018). Association between plasminogen activator inhibitor-1 and cardiovascular events: a systematic review and meta-analysis. Thromb J, 16(1):12.
25. Peng H, Yeh F, De SG, et al (2017). Relationship between plasma plasminogen activator inhibitor-1 and hypertension in American Indians: findings from the Strong Heart Study. J Hypertens, 35(9):1787-1793.
26. Smith L, Ralston-Hooper K, Ferguson P, Sabo-Attwood T (2016). The G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Nuclear Estrogen Receptor Activity and Stimulates Novel Phosphoproteomic Signatures. Toxicol Sci, 151(2):434-446.
27. Wang H, Sun X, Chou J, et al (2016). Cardiomyocyte-specific deletion of the G protein-coupled estrogen receptor (GPER) leads to left ventricular dysfunction and adverse remodeling: A sex-specific gene profiling analysis. Biochim Biophys Acta Mol Basis Dis, 1863(8):S0925443916302472.
28. Cosman F, Baz-Hecht M, Cushman M, et al (2005). Short-term effects of estrogen, tamoxifen and raloxifene on hemostasis: a randomized-controlled study and review of the literature. Thromb Res, 116(1):1-13.
29. Davis KE, Carstens EJ, Irani BG, Gent LM, Hahner LM, Clegg DJ (2014). Sexually dimorphic role of G protein-coupled estrogen receptor (GPER) in modulating energy homeostasis. Horm Behav, 66(1):196-207.
30. Suárez-Zamorano N, Fabbiano S, Chevalier C, et al (2015). Microbiota depletion promotes browning of white adipose tissue and reduces obesity. Nat Med, 21(12):1497-1501.
31. Hirose KK, Nakanishi M, Daimon N, et al (2021). Impact of insulin resistance on subclinical left ventricular dysfunction in normal weight and overweight/obese Japanese subjects in a general communi-ty. Cardiovasc Diabetol, 20(1): 22.
32. Bell DS, Goncalves E (2019). Heart failure in the patient with diabetes: Epidemiology, aetiology, prognosis, therapy and the effect of glucose‐lowering medications. Diabetes Obes Metab, 21(6):1277-1290.
33. Hattori Y (2020). Insulin resistance and heart failure during treatment with sodium glucose cotransporter 2 inhibitors: proposed role of ketone utilization. Heart Fail Rev, 25:403–408.
2. Najafi F, Dobson AJ, Hobbs M, Jamrozik K (2014). Temporal trends in the frequency and longer-term outcome of heart failure complicating myocardial infarction. Eur J Heart Fail, 9(9): 879-885.
3. Dharmarajan K, Hsieh AF, Kulkarni VT, et al (2015). Trajectories of risk after hospitalization for heart failure, acute myocardial infarction, or pneumonia: retrospective cohort study. BMJ, 350(feb05 19):h411.
4. Sartini S, Frizzi J, Borselli M, et al (2016). Which method is best for an early accurate diagnosis of acute heart failure? Comparison between lung ultrasound, chest X-ray and NT pro-BNP performance: a prospective study. Intern Emerg Med, 12(6):861-869.
5. Magnussen C, Blankenberg S (2018). Biomarkers for heart failure: small molecules with high clinical relevance. J Intern Med, 283(6):530-543.
6. Linssen GCM, Jaarsma T, Hillege HL, Voors AA, Veldhuisen DJV (2018). A comparison of the prognostic value of BNP versus NT-proBNP after hospitalisation for heart failure. Neth Heart J, 26(10):486-492.
7. Berezin AE, Kremzer AA, Martovitskaya YV, Berezina TA, Samura TA (2015). The utility of biomarker risk prediction score in patients with chronic heart failure. Int J Clin Exp Med,8(10):18255-64.
8. Ahmad FS, Ning H, Rich J, Lloyd-Jones D, Wilkins J (2016). Hypertension, obesity, diabetes, and heart failure-free survival: the cardiovascular lifetime risk pooling project. JACC Heart Fail, 4(12):911-919.
9. Lavie CJ, Sharma A, Alpert MA, et al (2016). Update on Obesity and Obesity Paradox in Heart Failure. Prog Cardiovasc Dis, 58(4):393-400.
10. Chrysant G S (2018). Obesity is bad regardless of the obesity paradox for hypertension and heart disease. J Clin Hypertens (Greenwich), 20(5):842-846.
11. Abhishek S, Lavie CJ, Borer JS, et al (2015). Meta-analysis of the relation of body mass index to all-cause and cardiovascular mortality and hospitalization in patients with chronic heart failure. Am J Cardiol, 115(10):1428-1434.
12. Elagizi A, Kachur S, Lavie C, et al (2018). An Overview and Update on Obesity and the Obesity Paradox in Cardiovascular Diseases. Prog Cardiovasc Dis, 61(2):142-150.
13. Patricia LL, Maria Luisa M, Marian Angeles Z, Jose Alfredo M (2013). SERPINE1, PAI-1 protein coding gene, methylation levels and epigenetic relationships with adiposity changes in obese subjects with metabolic syndrome features under dietary restriction. J Clin Biochem Nutr, 53(3):139-144.
14. Kaur P, Reis MD, Couchman GR, Forjuoh SN, Greene JF, Asea A (2010). SERPINE 1 Links Obesity and Diabetes: A Pilot Study. J Proteomics Bioinform, 3(6):191-99.
15. Langfelder P, Horvath S (2008). WGCNA: an R package for weighted correlation network analysis. BMC bioinformatics, 9(1):559.
16. Cao J, Zhang S (2014). Bayesian extension of the hypergeometric test for functional enrichment analysis. Biometrics, 70(1):84-94.
17. Matsushita M, Shirakabe A, Hata N, et al (2016). Association between the body mass index and the clinical findings in patients with acute heart failure: evaluation of the obesity paradox in patients with severely decompensated acute heart failure. Heart Vessels, 32(5): 600-608.
18. Alessi MC, Peiretti F, Morange P, Henry M, Nalbone G, Juhan-Vague I (1997). Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Diabetes, 46(5):860-867.
19. Juhan-Vague I, Alessi MC, Vague P (1991). Increased plasma plasminogen activator inhibitor 1 levels. A possible link between insulin resistance and atherothrombosis. Diabetologia, 34(7):457-462.
20. Andreas F, Ralph DA, Tracy RP, Haffner SM (2002). Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes, 51(4):1131-7.
21. Thomas K, Anatoly S, Ulrike R, Kurt J (2003). Hypoxia-inducible factor-1 and hypoxia response elements mediate the induction of plasminogen activator inhibitor-1 gene expression by insulin in primary rat hepatocytes. Blood, 101(3):907-914.
22. Tsai CH, Lee SS, Huang FM, Yu CC, Yang SF, Chang YC (2015). The modulation of hypoxia-inducible factor-1α/plasminogen activator inhibitor-1 axis in human gingival fibroblasts stimulated with cyclosporine A. J Formos Med Assoc, 114(1):58-63.
23. Kaikita K, Fogo AB, Ma L, Schoenhard JA, Brown NJ, Vaughan DE (2001). Plasminogen activator inhibitor-1 deficiency prevents hypertension and vascular fibrosis in response to long-term nitric oxide synthase inhibition. Circulation, 104(7):839-844.
24. Jung RG, Motazedian P, Ramirez FD, et al (2018). Association between plasminogen activator inhibitor-1 and cardiovascular events: a systematic review and meta-analysis. Thromb J, 16(1):12.
25. Peng H, Yeh F, De SG, et al (2017). Relationship between plasma plasminogen activator inhibitor-1 and hypertension in American Indians: findings from the Strong Heart Study. J Hypertens, 35(9):1787-1793.
26. Smith L, Ralston-Hooper K, Ferguson P, Sabo-Attwood T (2016). The G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Nuclear Estrogen Receptor Activity and Stimulates Novel Phosphoproteomic Signatures. Toxicol Sci, 151(2):434-446.
27. Wang H, Sun X, Chou J, et al (2016). Cardiomyocyte-specific deletion of the G protein-coupled estrogen receptor (GPER) leads to left ventricular dysfunction and adverse remodeling: A sex-specific gene profiling analysis. Biochim Biophys Acta Mol Basis Dis, 1863(8):S0925443916302472.
28. Cosman F, Baz-Hecht M, Cushman M, et al (2005). Short-term effects of estrogen, tamoxifen and raloxifene on hemostasis: a randomized-controlled study and review of the literature. Thromb Res, 116(1):1-13.
29. Davis KE, Carstens EJ, Irani BG, Gent LM, Hahner LM, Clegg DJ (2014). Sexually dimorphic role of G protein-coupled estrogen receptor (GPER) in modulating energy homeostasis. Horm Behav, 66(1):196-207.
30. Suárez-Zamorano N, Fabbiano S, Chevalier C, et al (2015). Microbiota depletion promotes browning of white adipose tissue and reduces obesity. Nat Med, 21(12):1497-1501.
31. Hirose KK, Nakanishi M, Daimon N, et al (2021). Impact of insulin resistance on subclinical left ventricular dysfunction in normal weight and overweight/obese Japanese subjects in a general communi-ty. Cardiovasc Diabetol, 20(1): 22.
32. Bell DS, Goncalves E (2019). Heart failure in the patient with diabetes: Epidemiology, aetiology, prognosis, therapy and the effect of glucose‐lowering medications. Diabetes Obes Metab, 21(6):1277-1290.
33. Hattori Y (2020). Insulin resistance and heart failure during treatment with sodium glucose cotransporter 2 inhibitors: proposed role of ketone utilization. Heart Fail Rev, 25:403–408.
| Files | ||
| Issue | Vol 54 No 7 (2025) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v54i7.19158 | |
| Keywords | ||
| Microarray Plasminogen activator inhibitor 1 Heart failure Obesity | ||
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How to Cite
1.
Zhu X, Hua J. Association of the Serpine1 with the Obesity Paradox in Ischemic Heart Failure. Iran J Public Health. 2025;54(7):1516-1529.
