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The Positive Regulation of eNOS Signaling by PPAR Agonists in Cardiovascular Diseases

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Abstract

Increasing evidence shows that activation of peroxisome proliferator-activated receptors (PPARs) plays an essential role in the regulation of vascular endothelial function through a range of mechanisms, including non-metabolic. Among these, the PPAR-mediated activation of endothelial nitric oxide synthase (eNOS) appears to be of considerable importance. The regulated and sustained bioavailability of nitric oxide (NO) in the endothelium is essential to avoid the development of cardiovascular diseases such as hypertension or atherosclerosis. Therefore, a deeper understanding of the different effects of specific PPAR ligands on NO bioavailability could be useful in the development of novel or multi-targeted PPAR agonists. In this review, we report the most meaningful and up-to-date in vitro and in vivo studies of the regulation of NO production performed by different PPAR agonists. Insights into the molecular mechanisms of PPAR-mediated eNOS activation are also provided. Although findings from animal studies in which the activation of PPARα, PPARβ/δ, or PPARγ have provided clear vasoprotective effects have been promising, several benefits from PPAR agonists are offset by unwanted outcomes. Therefore, new insights could be useful in the development of tissue-targeted PPAR agonists with more tolerable side effects to improve treatment options for cardiovascular diseases.

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References

  1. Cheang WS, Tian XY, Wong WT, et al. The peroxisome proliferator-activated receptors in cardiovascular diseases: experimental benefits and clinical challenges. Br J Pharmacol. 2015;172:5512–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Gilde AJ, van der Lee KA, Willemsen PH, et al. Peroxisome proliferator-activated receptor (PPAR) alpha and PPARbeta/delta, but not PPARgamma, modulate the expression of genes involved in cardiac lipid metabolism. Circ Res. 2003;92:518–24.

    Article  CAS  PubMed  Google Scholar 

  3. Finck BN, Chinetti G, Staels B. PPARs/RXRs in cardiovascular physiology and disease. PPAR Res. 2008;2008:173780. doi:10.1155/2008/173780.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Huss JM, Kelly DP. Nuclear receptor signaling and cardiac energetics. Circ Res. 2004;95:568–78.

    Article  CAS  PubMed  Google Scholar 

  5. Huss JM, Kelly DP. Mitochondrial energy metabolism in heart failure: a question of balance. J Clin Invest. 2005;115:547–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yang Q, Li Y. Roles of PPARs on regulating myocardial energy and lipid homeostasis. J Mol Med. 2007;85:697–706.

    Article  CAS  PubMed  Google Scholar 

  7. Madrazo JA, Kelly DP. The PPAR trio: regulators of myocardial energy metabolism in health and disease. J Mol Cell Cardiol. 2008;44:968–75.

    Article  CAS  PubMed  Google Scholar 

  8. Pirat C, Farce A, Lebegue N, et al. Targeting peroxisome proliferator activated receptors (PPARs): development of modulators. J Med Chem. 2012;55:4027–61.

    Article  CAS  PubMed  Google Scholar 

  9. Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med. 2002;53:409–35.

    Article  CAS  PubMed  Google Scholar 

  10. Murad F. Discovery of some of the biological effects of nitric oxide and its role in cell signaling. Biosci Rep. 2004;24:452–74.

    Article  PubMed  Google Scholar 

  11. Malinski T. Understanding nitric oxide physiology in the heart: a nanomedical approach. Am J Cardiol. 2005;96:13i–24i.

    Article  CAS  PubMed  Google Scholar 

  12. Fantacuzzi M, Maccallini C, Lannutti F, et al. Selective inhibition of iNOS by benzyl- and dibenzyl derivatives of N-(3-Aminobenzyl) acetamidine. Chem Med Chem. 2011;6:1203–6.

    Article  CAS  PubMed  Google Scholar 

  13. Patruno A, Franceschelli S, Pesce M, et al. Novel aminobenzyl-acetamidine derivative modulate the differential regulation of NOSs in LPS induced inflammatory response: role of PI3K/Akt pathway. Biochim Biophys Acta. 2012;1820:2095–104.

    Article  CAS  PubMed  Google Scholar 

  14. Maccallini C, Montagnani M, Paciotti R, et al. Selective acetamidine-based nitric oxide synthase inhibitors: synthesis, docking, and biological studies. ACS Med Chem Lett. 2015;6:635–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Qian J, Fulton D. Post-translational regulation of endothelial nitric oxide synthase in vascular endothelium. Front Physiol. 2013;4:347.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Rudic RD, Shesely EG, Maeda N, et al. Direct evidence for the importance of endothelium derived nitric oxide in vascular remodeling. J Clin Invest. 1998;101:731–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Shesely G, Nobuyo M, Kim S, et al. Elevated blood pressures in mice lacking endothelial nitric oxide synthase. Proc Natl Acad Sci. 1996;93:13176–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Schade D, Kotthaus J, Clement B. Modulating the NO generating system from a medicinal chemistry perspective: current trends and therapeutic options in cardiovascular disease. Pharmacol Ther. 2010;126:279–300.

    Article  CAS  PubMed  Google Scholar 

  19. Francis GA, Fayard E, Picard F, et al. Nuclear receptors and the control of metabolism. Annu Rev Physiol. 2003;65:261–311.

    Article  CAS  PubMed  Google Scholar 

  20. Watanabe K, Fujii H, Takahashi T, et al. Constitutive regulation of cardiac fatty acid metabolism through peroxisome proliferator-activated receptor α associated with age-dependent cardiac toxicity. J Biol Chem. 2000;275:22293–9.

    Article  CAS  PubMed  Google Scholar 

  21. Guellich A, Damy T, Lecarpentier Y, et al. Role of oxidative stress in cardiac dysfunction of PPARα −/− mice. Am J Physiol Heart Circ Physiol. 2007;293:H93–102.

    Article  CAS  PubMed  Google Scholar 

  22. Keller DI, Coirault C, Rau T, et al. Human homozygous R403W mutant cardiac myosin presents disproportionate enhancement of mechanical and enzymatic properties. J Mol Cell Cardiol. 2004;36:355–62.

    Article  CAS  PubMed  Google Scholar 

  23. Barger PM, Brandt JM, Leone TC, et al. Deactivation of peroxisome proliferator-activated receptor-alpha during cardiac hypertrophic growth. J Clin Invest. 2000;105:1723–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Karbowska J, Kochan Z, Smolenski RT. Peroxisome proliferator-activated receptor α is downregulated in the failing human heart. Cell Mol Biol Lett. 2003;8:49–53.

    CAS  PubMed  Google Scholar 

  25. Yousefipour Z, Newaz M. PPARα ligand clofibrate ameliorates blood pressure and vascular reactivity in spontaneously hypertensive rats. Acta Pharmacol Sinica. 2014;35:476–82.

    Article  CAS  Google Scholar 

  26. Lecarpentier Y, Claes V, Hebert JL. PPARs, cardiovascular metabolism, and function: near or far from equilibrium pathways. PPAR Res. doi:10.1155/2010/783273 (epub 27 July 2010).

  27. Poynter ME, Daynes RA. Peroxisome proliferator activated receptor α activation modulates cellular redox status, represses nuclear factor-κB signaling, and reduces inflammatory cytokine production in aging. J Biol Chem. 1998;273:32833–41.

    Article  CAS  PubMed  Google Scholar 

  28. Atherton HJ, Gulston MK, Bailey NJ, et al. Metabolomics of the interaction between PPAR-α and age in the PPAR-α-null mouse. Mol Sys Biol. 2009;5:259.

    Google Scholar 

  29. Katsiki N, Nikolic D, Montalto G, et al. The role of fibrate treatment in dyslipidemia: an overview. Curr Pharm Des. 2013;19:3124–31.

    Article  CAS  PubMed  Google Scholar 

  30. De Filippis B, Giancristofaro A, Ammazzalorso A, et al. Discovery of gemfibrozil analogues that activate PPARα and enhance the expression of gene CPT1A involved in fatty acids catabolism. Eur J Med Chem. 2011;46:5218–24.

    Article  PubMed  Google Scholar 

  31. Giampietro L, D’Angelo A, Giancristofaro A, et al. Synthesis and structure-activity relationships of fibrate-based analogues inside PPARs. Bioorg Med Chem Lett. 2012;22:7662–6.

    Article  CAS  PubMed  Google Scholar 

  32. Giampietro L, D’Angelo A, Giancristofaro A, et al. Effect of stilbene and chalcone scaffolds incorporation in clofibric acid on PPARα agonistic activity. Med Chem. 2014;10:59–65.

    Article  CAS  PubMed  Google Scholar 

  33. Ibarra-Lara L, Del Valle-Mondragon L, Soria-Castro E, et al. Peroxisome proliferator-activated receptor-α stimulation by clofibrate favors an antioxidant and vasodilator environment in a stressed left ventricle. Pharmacol Rep. 2016;68:692–702.

    Article  CAS  PubMed  Google Scholar 

  34. Wang Y, Wang Y, Yang Q, et al. Effects of bezafibrate on the expression of endothelial nitric oxide synthase gene and its mechanisms in cultured bovine endothelial cells. Atherosclerosis. 2006;187:265–73.

    Article  CAS  PubMed  Google Scholar 

  35. Goya K, Sumitani S, Xu X, et al. Peroxisome proliferator activated receptor α agonists increase nitric oxide synthase expression in vascular endothelial cells. Arterioscler Thromb Vasc Biol. 2004;24:658–63.

    Article  CAS  PubMed  Google Scholar 

  36. Okayasu T, Tomizawa A, Suzuki K, et al. PPARα activators upregulate eNOS activity and inhibit cytokine-induced NF-κB activation through AMP-activated protein kinase activation. Life Sci. 2008;82:884–91.

    Article  CAS  PubMed  Google Scholar 

  37. Walker AE, Kaplon RE, Lucking SM, et al. Fenofibrate improves vascular endothelial function by reducing oxidative stress while increasing enos in healthy normolipidemic older adults. Hypertension. 2012;60:1517–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Förstermann U, Li H. Therapeutic effect of enhancing endothelial nitric oxide synthase (eNOS) expression and preventing eNOS uncoupling. Br J Pharmacol. 2011;164:213–23.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Liu J, Lu C, Li F, et al. PPAR-α agonist fenofibrate upregulates tetrahydrobiopterin level through increasing the expression of guanosine 5′-triphosphate cyclohydrolase-I in human umbilical vein endothelial cells. PPAR Res. 2011;2011:523520. doi:10.1155/2011/523520.

    PubMed  PubMed Central  Google Scholar 

  40. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317:1237–45.

    Article  CAS  PubMed  Google Scholar 

  41. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999;341:410–8.

    Article  CAS  PubMed  Google Scholar 

  42. Guo Q, Wang G, Liu X, et al. Effects of gemfibrozil on outcome after permanent middle cerebral artery occlusion in mice. Brain Res. 2009;1279:121–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sharina IG, Sobolevsky M, Papakyriakou A, et al. The fibrate gemfibrozil is a NO- and haem-independent activator of soluble guanylyl cyclase: in vitro studies. Br J Pharmacol. 2015;172:2316–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Barish GD, Narkar VA, Evans RM. PPAR delta: a dagger in the heart of the metabolic syndrome. J Clin Invest. 2006;116:590–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bishop-Bailey D, Bystrom J. Emergimg roles of peroxisome proliferator-activated receptor-beta/delta in inflammation. Pharmacol Ther. 2009;124:141–50.

    Article  CAS  PubMed  Google Scholar 

  46. Riserus U, Sprecher D, Johnson T, et al. Activation of peroxisome proliferator-activated receptor (PPAR)delta promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men. Diabetes. 2008;57:332–9.

    Article  CAS  PubMed  Google Scholar 

  47. Sznaidman ML, Haffner CD, Maloney PR, et al. Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta): synthesis and biological activity. Bioorg Med Chem Lett. 2003;13:1517–21.

    Article  CAS  PubMed  Google Scholar 

  48. Oliver WRJ, Shenk JL, Snaith RM, et al. A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport. Proc Natl Acad Sci USA. 2001;98(9):5306–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Xu HE, Lambert MH, Montana VG, et al. Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA. 2001;98:13919–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sheng L, Ye P, Liu YX, et al. Peroxisome proliferator activated receptor beta/delta activation improves angiotensin II-induced cardiac hypertrophy in vitro. Clin Exp Hypertens. 2008;30:109–19.

    Article  CAS  PubMed  Google Scholar 

  51. Jiang B, Liang P, Zhang B, et al. Role of PPAR-beta in hydrogen peroxide-induced apoptosis in human umbilical vein endothelial cells. Atherosclerosis. 2009;204:353–8.

    Article  CAS  PubMed  Google Scholar 

  52. Lim HJ, Lee S, Park JH, et al. PPAR agonist L-165041 inhibits rat vascular smooth muscle cell proliferation and migration via inhibition of cell cycle. Atherosclerosis. 2009;202:446–54.

    Article  CAS  PubMed  Google Scholar 

  53. Quintela AM, Jiménez R, Piqueras L, et al. PPARβ activation restores the high glucose-induced impairment of insulin signalling in endothelial cells. Br J Pharmacol. 2014;171:3089–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. He T, Smith LA, Lu T, et al. Activation of peroxisome proliferator-activated receptor–delta enhances regenerative capacity of human endothelial progenitor cells by stimulating biosynthesis of tetrahydrobiopterin. Hypertension. 2011;58:287–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Santhanam AVR, d’Uscio LV, He T, et al. Uncoupling of endothelial nitric oxide synthase in cerebral vasculature of Tg2576 mice. J Neurochem. 2015;134:1129–38.

    Article  CAS  PubMed  Google Scholar 

  56. Xu HE, Lambert MH, Montana VG, et al. Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA. 2001;98:13919–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Gampe RT Jr, Montana VG, Lambert MH, et al. Asymmetry in the PPARγ/RXRα crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Mol Cell. 2000;5:545–55.

    Article  CAS  PubMed  Google Scholar 

  58. Wang N, Yang G, Jia Z, et al. Vascular PPARγ controls circadian variation in blood pressure and heart rate through Bmal1. Cell Metab. 2008;8:482–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Anan F, Masaki T, Fukunaga N, et al. Pioglitazone shift circadian rhythm of blood pressure from non-dipper to dipper type in type 2 diabetes mellitus. Eur J Clin Invest. 2007;37:709–14.

    Article  CAS  PubMed  Google Scholar 

  60. van Bilsen M, van Nieuwenhoven FA. PPARs as therapeutic targets in cardiovascular disease. Expert Opin Ther Target. 2010;14:1029–45.

    Article  Google Scholar 

  61. Polikandriotis JA, Mazzella LJ, Rupnow HL, et al. Peroxisome proliferator-activated receptor gamma ligands stimulate endothelial nitric oxide production through distinct peroxisome proliferator-activated receptor gamma-dependent mechanisms. Arterioscler Thromb Vasc Biol. 2005;25:1810–6.

    Article  CAS  PubMed  Google Scholar 

  62. Hwang J, Kleinhenz DJ, Lassègue B. Peroxisome proliferator-activated receptor-gamma ligands regulate endothelial membrane superoxide production. Am J Physiol Cell Physiol. 2005;288:C899–905.

    Article  CAS  PubMed  Google Scholar 

  63. Hur W, Gray NS. Small molecule modulators of antioxidant response pathway. Curr Opin Chem Biol. 2011;15:162–3.

    Article  CAS  PubMed  Google Scholar 

  64. Luo Z, Aslam S, Welch WJ, et al. Activation of nuclear factor erythroid 2-related factor 2 coordinates dimethylarginine dimethylaminohydrolase/PPAR-γ/endothelial nitric oxide synthase pathways that enhance nitric oxide generation in human glomerular endothelial cells. Hypertension. 2015;65:896–902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Polvani S, Tarocchi M, Galli A. PPARγ and oxidative stress: Con(β) catenating NRF2 and FOXO. PPAR Res. 2012;2012:641087. doi:10.1155/2012/641087/.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Li R, Zhang H, Wang W, et al. Vascular insulin resistance in prehypertensive rats: role of PI3-kinase/Akt/eNOS signaling. Eur J Pharmacol. 2010;628:140–7.

    Article  CAS  PubMed  Google Scholar 

  67. Wong WT, Tian XY, Xu A, et al. Adiponectin is required for PPARγ-mediated improvement of endothelial function in diabetic mice. Cell Metab. 2011;14:104–15.

    Article  CAS  PubMed  Google Scholar 

  68. Xu L, Wang S, Li B, et al. A protective role of ciglitazone in ox-LDL-induced rat microvascular endothelial cells via modulating PPARγ-dependent AMPK/eNOS pathway. J Cell Mol Med. 2015;19:92–102.

    Article  CAS  PubMed  Google Scholar 

  69. Nohria A, Grunert ME, Rikitake Y, et al. Rho kinase inhibition improves endothelial function in human subjects with coronary artery disease. Circ Res. 2006;99:1426–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wakino S, Hayashi K, Kanda T, et al. Peroxisome proliferator-activated receptor gamma ligands inhibit Rho/Rho kinase pathway by inducing protein tyrosine phosphatase SHP-2. Circ Res. 2004;95:e45–55.

    Article  CAS  PubMed  Google Scholar 

  71. Ghosh A, Sahana PK, Das C, et al. Comparison of effectiveness and safety of add-on therapy of saroglitazar and fenofibrate with metformin in indian patients with diabetic dyslipidaemia. J Clin Diagn Res. 2016;10:FC01.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Deshpande A, Toshniwal H, Joshi S, et al. A prospective, multicentre, open-label single-arm exploratory study to evaluate efficacy and safety of saroglitazar on hypertriglyceridemia in HIV associated lipodystrophy. PLoS One. 2016;11:e0146222.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Shetty SR, Kumar S, Mathur RP, et al. Observational study to evaluate the safety and efficacy of saroglitazar in Indian diabetic dyslipidemia patients. Indian Heart J. 2015;67:23–6.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Pai V, Paneerselvam A, Mukhopadhyay S, et al. A multicenter, prospective, randomized, double-blind study to evaluate the safety and efficacy of saroglitazar 2 and 4 mg compared to pioglitazone 45 mg in diabetic dyslipidemia (PRESS V). J Diabetes Sci Technol. 2014;8:132–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Jani RH, Pai V, Jha P, et al. A multicenter, prospective, randomized, double-blind study to evaluate the safety and efficacy of Saroglitazar 2 and 4 mg compared with placebo in type 2 diabetes mellitus patients having hypertriglyceridemia not controlled with atorvastatin therapy (PRESS VI). Diabetes Technol Ther. 2014;16:63–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Jani RH, Kansagra K, Jain MR, et al. Pharmacokinetics, safety, and tolerability of saroglitazar (ZYH1), a predominantly PPARα agonist with moderate PPARγ agonist activity in healthy human subjects. Clin Drug Investig. 2013;33:809–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Jun M, Zhu B, Tonelli M, et al. Effects of fibrates in kidney disease: a systematic review and meta-analysis. J Am Coll Cardiol. 2012;60:2061–71.

    Article  CAS  PubMed  Google Scholar 

  78. Davis TME, Ting R, Best JD. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event lowering in diabetes (FIELD) study. Diabetologia. 2011;54:280–90.

    Article  CAS  PubMed  Google Scholar 

  79. Hottelart C, El Esper N, Rose F, et al. Fenofibrate increases creatininemia by increasing metabolic production of creatinine. Nephron. 2002;92:536–41.

    Article  CAS  PubMed  Google Scholar 

  80. Pollock CB, Rodriguez O, Martin PL, et al. Induction of metastatic gastric cancer by peroxisome proliferator-activated receptor δ activation. PPAR Res. 2010;2010:571783. doi:10.1155/2010/571783.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Peraza MA, Burdik AD, Marin HE, et al. The toxicology of ligands for peroxisome proliferator-activated receptors (PPAR). Toxicol Sci. 2006;90:269–95.

    Article  CAS  PubMed  Google Scholar 

  82. Vallarino C, Perez A, Fusco G, et al. Comparing pioglitazone to insulin with respect to cancer, cardiovascular and bone fracture endpoints, using propensity score weights. Clin Drug Investig. 2013;33:621–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Balakumar P, Jagadeesh G. PPAR ligands and cardiovascular disorders: friend or foe. Curr Mol Pharmacol. 2012;5:219–23.

    Article  CAS  PubMed  Google Scholar 

  84. Lu L, Reiter MJ, Xu Y, et al. Thiazolidinedione drugs block cardiac KATP channels and may increase propensity for ischaemic ventricular fibrillation in pigs. Diabetologia. 2008;51:675–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Erdmann E, Harding S, Lam H, Perez A. Ten-year observational follow-up of PROactive: a randomized cardiovascular outcomes trial evaluating pioglitazone in type 2 diabetes. Diabetes Obes Metab. 2016;18:266–73.

    Article  CAS  PubMed  Google Scholar 

  86. Wright MB, Bortolini M, Tadayyon M, Bopst M. Challenges and Opportunities in Development of PPAR Agonists. Mol Endocrinol. 2014;28:1756–68.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Balakumar P, Kathuria S. Submaximal PPARγ activation and endothelial dysfunction: new perspectives for the management of cardiovascular disorders. Br J Pharmacol. 2012;166:1981–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, Via dei Vestini 31, 66100, Chieti, Italy

    Cristina Maccallini, Adriano Mollica & Rosa Amoroso

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  1. Cristina Maccallini
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Correspondence to Cristina Maccallini.

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Dr Maccallini, Professor Mollica, and Professor Amoroso have no conflicts of interest that are relevant to the content of this review.

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Maccallini, C., Mollica, A. & Amoroso, R. The Positive Regulation of eNOS Signaling by PPAR Agonists in Cardiovascular Diseases. Am J Cardiovasc Drugs 17, 273–281 (2017). https://doi.org/10.1007/s40256-017-0220-9

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