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Therapeutic Targeting of Cellular Stress to Prevent Cardiovascular Disease: A Review of the Evidence

Abstract

The availability of effective drugs targeting the major risk factors of cardiovascular disease (CVD) has reduced morbidity and mortality. Cumulative relative risk of CVD events can be reduced by 75 % with a combination of aspirin, a β-adrenoceptor antagonist (β-blocker), an HMG-CoA reductase inhibitor (statin), and an angiotensin-converting enzyme inhibitor. The principal pharmacodynamics of these drugs cannot explain the entirety of their cardioprotective action, as other drugs with similar pharmacologic targets have not been associated with favorable clinical effects. This raises the possibility that the cardioprotective drugs have a unique pleiotropic activity that contributes to their clinical efficacy. Recent data suggest that reducing cellular stress such as oxidative, inflammatory, and endoplasmic reticulum stress, might be a common denominator of the drugs with proven efficacy in reducing CVD risk. In this communication, the evidence in favor of this hypothesis is discussed, and ongoing trials with therapeutic agents targeting cellular stresses are reviewed.

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References

  1. Gregg EW, Li Y, Wang J, Burrows NR, Ali MK, Rolka D, Williams DE, Geiss L. Changes in diabetes-related complications in the United States, 1990–2010. N Engl J Med. 2014;370:1514–23.

    CAS  PubMed  Article  Google Scholar 

  2. Johnson NB, Hayes LD, Brown K, Hoo EC, Ethier KA, Centers for Disease Control and Prevention (CDC). CDC National Health Report: leading causes of morbidity and mortality and associated behavioral risk and protective factors–United States, 2005–2013. MMWR Surveill Summ. 2014;63(Suppl 4):3–27.

    Google Scholar 

  3. Yusuf S. Two decades of progress in preventing vascular disease. Lancet. 2002;360:2–3.

    PubMed  Article  Google Scholar 

  4. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981–97.

    Article  Google Scholar 

  5. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. Rosendorff C, On behalf of the Writing Committee. Treatment of hypertension in patients with coronary artery disease. A case-based summary of the 2015 AHA/ACC/ASH scientific statement. Am J Med. 2016;129:372–8.

    PubMed  Article  Google Scholar 

  7. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854–65.

    Article  Google Scholar 

  8. Zinman B, Wanner C, Lachin JM, For the EMPA-REG OUTCOME Investigators, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128.

  9. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837–53.

    Article  Google Scholar 

  10. ACCORD Study Group, Gerstein HC, Miller ME, Genuth S, et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011;364:818–28.

    Article  Google Scholar 

  11. Reusch JE, Wang CC. Cardiovascular disease in diabetes: where does glucose fit in? J Clin Endocrinol Metab. 2011;96:2367–76.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet. 2009;373:1765–72.

    CAS  PubMed  Article  Google Scholar 

  13. Hayward RA, Reaven PD, Wiitala WL, et al. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;372:2197–206.

    CAS  PubMed  Article  Google Scholar 

  14. Kojanian H, Szafran-Swietlik A, Onstead-Haas LM, Haas MJ, Mooradian AD. Statins prevent dextrose-induced endoplasmic reticulum stress and oxidative stress in endothelial and HepG2 cells. Am J Ther. 2014 [Epub ahead of print].

  15. Haas MJ, Horani MH, Parseghian SA, Mooradian AD. Statins prevent dextrose-induced endothelial barrier dysfunction, possibly through inhibition of superoxide formation. Diabetes. 2006;55:474–9.

    CAS  PubMed  Article  Google Scholar 

  16. Haas MJ, Kurban W, Shah H, Onstead-Haas L, Mooradian AD. Beta blockers suppress dextrose-induced endoplasmic reticulum stress, oxidative stress, and apoptosis in human coronary artery endothelial cells. Am J Ther. 2015 [Epub ahead of print].

  17. Horani MH, Haas MJ, Mooradian AD. Suppression of hyperglycemia-induced superoxide formation and endothelin-1 gene expression by carvedilol. Am J Ther. 2006;13:2–7.

    PubMed  Article  Google Scholar 

  18. Fahlbusch SA, Tsikas D, Mehls C, et al. Effects of carvedilol on oxidative stress in human endothelial cells and healthy volunteers. Eur J Clin Pharmacol. 2004;60:83–8.

    CAS  PubMed  Article  Google Scholar 

  19. Chan S, Chen MP, Cao JM, Chan GC, Cheung YF. Carvedilol protects against iron-induced microparticle generation and apoptosis of endothelial cells. Acta Haematol. 2014;132:200–10.

    CAS  PubMed  Article  Google Scholar 

  20. Nickenig G, Harrison DG. The AT1-type angiotensin receptor in oxidative stress and atherogenesis, part I: oxidative stress and atherogenesis. Circulation. 2002;105:393–6.

    CAS  PubMed  Article  Google Scholar 

  21. Sowers JR. Hypertension, angiotensin II, and oxidative stress. N Engl J Med. 2002;346:1999–2001.

    PubMed  Article  Google Scholar 

  22. Nguyen Dinh Cat A, Montezano AC, Burger D, Touyz RM. Angiotensin II, NADPH oxidase, and redox signaling in the vasculature. Antioxid Redox Signal. 2013;19:1110–20.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Zhang H, Schmeisser A, Garlichs CD, et al. Angiotensin II-induced superoxide anion generation in human vascular endothelial cells: role of membrane-bound NADH-/NADPH-oxidases. Cardiovasc Res. 1999;44:215–22.

    CAS  PubMed  Article  Google Scholar 

  24. Haas MJ, Onstead-Haas L, Lee T, Torfah M, Mooradian AD. Angiotensin II receptor one (AT1) mediates dextrose induced endoplasmic reticulum stress and superoxide production in human coronary artery endothelial cells. Int J Cardiol. 2016;220:842–50.

    PubMed  Article  Google Scholar 

  25. Mooradian AD. Targeting select cellular stress pathways to prevent hyperglycemia-related complications: shifting the paradigm. Drugs. 2016;76:1081–91.

    PubMed  Article  CAS  Google Scholar 

  26. Cominacini L, Mozzini C, Garbin U, et al. Endoplasmic reticulum stress and Nrf2 signaling in cardiovascular diseases. Free Radic Biol Med. 2015;88(Pt B):233–242.

  27. Myoishi M, Hao H, Minamino T, et al. Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome. Circulation. 2007;116:1226–33.

    PubMed  Article  Google Scholar 

  28. Buchwald H, Varco RL, Matts JP, et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH). N Engl J Med. 1990;323:946–55.

    CAS  PubMed  Article  Google Scholar 

  29. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomized trials of statins: a meta-analysis. Lancet. 2008;371:117–125.

  30. HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371:203–212.

  31. The AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–67.

    Article  CAS  Google Scholar 

  32. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387–97.

    CAS  PubMed  Article  Google Scholar 

  33. Egom EE. Ezetimibe plus a statin after acute coronary syndromes. N Engl J Med. 2015;373:1474.

    PubMed  Google Scholar 

  34. Yamaoka-Tojo M, Tojo T, Takahira N, Masuda T, Izumi T. Ezetimibe and reactive oxygen species. Curr Vasc Pharmacol. 2011;9:109–20.

    CAS  PubMed  Article  Google Scholar 

  35. Pesaro AE, Serrano CV Jr, Fernandes JL, et al. Pleiotropic effects of ezetimibe/simvastatin vs. high dose simvastatin. Int J Cardiol. 2012;158:400–4.

    PubMed  Article  Google Scholar 

  36. Kater AL, Batista MC, Ferreira SR. Synergistic effect of simvastatin and ezetimibe on lipid and pro-inflammatory profiles in pre-diabetic subjects. Diabetol Metab Syndr. 2010;2:34.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  37. Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370:1809–19.

    CAS  PubMed  Article  Google Scholar 

  38. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489–99.

    CAS  PubMed  Article  Google Scholar 

  39. Laufs U, Marra D, Node K, Liao JK. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors attenuate vascular smooth muscle proliferation by preventing Rho GTPase-induced down-regulation of p27Kip1. J Biol Chem. 1999;274:21926–31.

    CAS  PubMed  Article  Google Scholar 

  40. Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem. 1998;273:24266–71.

    CAS  PubMed  Article  Google Scholar 

  41. Wassmann S, Laufs U, Bäumer AT, et al. HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species. Hypertension. 2001;37:1450–7.

    CAS  PubMed  Article  Google Scholar 

  42. Wassmann S, Laufs U, Müller K, et al. Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler Thromb Vasc Biol. 2002;22:300–5.

    CAS  PubMed  Article  Google Scholar 

  43. DiNicolantonio JJ, Fares H, Niazi AK, et al. β-Blockers in hypertension, diabetes, heart failure and acute myocardial infarction: a review of the literature. Open Heart. 2015;2(1):e000230.

    PubMed  PubMed Central  Article  Google Scholar 

  44. Winchester DE, Pepine CJ. Usefulness of beta blockade in contemporary management of patients with stable coronary heart disease. Am J Cardiol. 2014;114:1607–12.

    PubMed  Article  Google Scholar 

  45. Malhotra S, Das MK. Delayed and indirect effects of antiarrhythmic drugs in reducing sudden cardiac death. Future Cardiol. 2011;7:203–17.

    CAS  PubMed  Article  Google Scholar 

  46. Opie LH, Yusuf S, Kübler W. Current status of safety and efficacy of calcium channel blockers in cardiovascular diseases: a critical analysis based on 100 studies. Prog Cardiovasc Dis. 2000;43:171–96.

    CAS  PubMed  Article  Google Scholar 

  47. Godfraind TJ. Calcium channel blockers in cardiovascular pharmacotherapy. Cardiovasc Pharmacol Ther. 2014;19:501–15.

    CAS  Article  Google Scholar 

  48. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376:875–85.

    CAS  PubMed  Article  Google Scholar 

  49. Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R, SIGNIFY Investigators. Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med. 2014;371:1091–9.

    PubMed  Article  CAS  Google Scholar 

  50. Ohman EM, Alexander KP. The challenges with chronic angina. N Engl J Med. 2014;371:1152–3.

    PubMed  Article  CAS  Google Scholar 

  51. Turan B. A comparative summary on antioxidant-like actions of timolol with other antioxidants in diabetic cardiomyopathy. Curr Drug Deliv. 2016;13:418–23.

    CAS  PubMed  Article  Google Scholar 

  52. Obadah M, Al Chekakie AI. Traditional heart failure medications and sudden cardiac death prevention: a review. J Cardiovas Pharmacol Therap. 2012;18:412–26.

    Google Scholar 

  53. Bender SB, Jia G, Sowers JR. Mineralocorticoid receptors: an appealing target to treat coronary microvascular dysfunction in diabetes. Diabetes. 2015;64:3–5.

    CAS  PubMed  Article  Google Scholar 

  54. Garg R, Rao AD, Baimas-George M, et al. Mineralocorticoid receptor blockade improves coronary microvascular function in individuals with type 2 diabetes. Diabetes. 2015;64:236–42.

    CAS  PubMed  Article  Google Scholar 

  55. Reboldi G, Angeli F, Cavallini C, Gentile G, Mancia G, Verdecchia P. Comparison between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk of myocardial infarction, stroke and death: a meta-analysis. J Hypertens. 2008;26:1282–9.

    CAS  PubMed  Article  Google Scholar 

  56. Dagenais GR, Pogue J, Fox K, Simoons ML, Yusuf S. Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials. Lancet. 2006;368:581–8.

    CAS  PubMed  Article  Google Scholar 

  57. Zheng Z, Chen H, Ke G, et al. Protective effect of perindopril on diabetic retinopathy is associated with decreased vascular endothelial growth factor–to–pigment epithelium–derived factor ratio. Involvement of a mitochondria–reactive oxygen species pathway. Diabetes. 2009;58:954–64.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Lv J, Perkovic V, Foote CV, Craig ME, Craig JC, Strippoli GF. Antihypertensive agents for preventing diabetic kidney disease. Cochrane Database Syst Rev. 2012;12:CD004136.

  59. Dhakarwal P, Agrawal V, Kumar A, Goli KM, Agrawal V. Update on role of direct renin inhibitor in diabetic kidney disease. Ren Fail. 2014;36:963–9.

    PubMed  Article  Google Scholar 

  60. Parviz Y, Iqbal J, Pitt B, Adlam D, Al-Mohammad A, Zannad F. Emerging cardiovascular indications of mineralocorticoid receptor antagonists. Trends Endocrinol Metab. 2015;26:201–11.

    CAS  PubMed  Article  Google Scholar 

  61. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–17.

    CAS  PubMed  Article  Google Scholar 

  62. Pitt B, Remme W, Zannad F, Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309–21.

    CAS  PubMed  Article  Google Scholar 

  63. McMurray JJ, Krum H, Abraham WT, et al. Aliskiren, enalapril, or aliskiren and enalapril in heart failure. N Engl J Med. 2016;374:1521–32.

    CAS  PubMed  Article  Google Scholar 

  64. Lin C, Zhang Q, Zhang H, Lin A. Long-term effects of low-dose spironolactone on chronic dialysis patients: a randomized placebo-controlled study. J Clin Hypertens. 2016;18:121–8.

    CAS  Article  Google Scholar 

  65. Pilgrim T, Windecker S. Antiplatelet therapy for secondary prevention of coronary artery disease. Heart. 2014;100:1750–6.

    CAS  PubMed  Article  Google Scholar 

  66. Cheng JW. Updates in antiplatelet agents used in cardiovascular diseases. J Cardiovasc Pharmacol Ther. 2013;18:514–24.

    CAS  PubMed  Article  Google Scholar 

  67. Palacio S, Hart RG, Pearce LA, Benavente OR. Effect of addition of clopidogrel to aspirin on mortality: systematic review of randomized trials. Stroke. 2012;43:2157–62.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Schnorbus B, Daiber A, Jurk K, et al. Effects of clopidogrel, prasugrel and ticagrelor on endothelial function, inflammatory and oxidative stress parameters and platelet function in patients undergoing coronary artery stenting for an acute coronary syndrome. A randomised, prospective, controlled study. BMJ Open. 2014;4:e005268.

  69. Gawron-Skarbek A, Chrzczanowicz J, Kostka J, et al. Factors determining the total serum antioxidant capacity in men with coronary heart disease–the powerful effect of treatment with thienopyridines. Nutr Metab Cardiovasc Dis. 2014;24:e21–3.

    CAS  PubMed  Article  Google Scholar 

  70. Heitzer T, Rudolph V, Schwedhelm E, et al. Clopidogrel improves systemic endothelial nitric oxide bioavailability in patients with coronary artery disease: evidence for antioxidant and antiinflammatory effects. Arterioscler Thromb Vasc Biol. 2006;26:1648–52.

    CAS  PubMed  Article  Google Scholar 

  71. Hawley SA, Fullerton MD, Ross FA, et al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science. 2012;336:918–22.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. Yang H, Zhao P, Tian S. Clopidogrel protects endothelium by hindering TNFα-induced VCAM-1 expression through CaMKKβ/AMPK/Nrf2 pathway. J Diabetes Res. 2016;2016:9128050.

    PubMed  Google Scholar 

  73. Hadi NR, Mohammad BI, Ajeena IM, Sahib HH. Antiatherosclerotic potential of clopidogrel: antioxidant and anti-inflammatory approaches. BioMed Res Int. 2013;2013:790263.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. Hattori Y, Hattori K, Hayashi T. Pleiotropic benefits of metformin: Macrophage targeting its anti-inflammatory mechanisms. Diabetes. 2015;16:1907–9.

    Article  CAS  Google Scholar 

  75. Batandier C, Guigas B, Detaille D, et al. The ROS production induced by a reverse-electron flux at respiratory-chain complex 1 is hampered by metformin. J Bioenerg Biomembr. 2006;38:33–42.

    CAS  PubMed  Article  Google Scholar 

  76. Hirsch HA, Iliopoulos D, Struhl K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Natl Acad Sci. 2013;110:972–7.

    CAS  PubMed  Article  Google Scholar 

  77. Shang F, Zhang J, Li Z, et al. Cardiovascular protective effect of metformin and telmisartan: reduction of PARP1 activity via the AMPK-PARP1 cascade. PLoS One. 2016;11(3):e0151845.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  78. de Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med. 2013;369:2492–503.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  79. Chen T, Jin X, Crawford BH, et al. Cardioprotection from oxidative stress in the newborn heart by activation of PPARγ is mediated by catalase. Free Radic Biol Med. 2012;53:208–15.

    PubMed  Article  CAS  Google Scholar 

  80. Mizoguchi M, Tahara N, Tahara A, et al. Pioglitazone attenuates atherosclerotic plaque inflammation in patients with impaired glucose tolerance or diabetes a prospective, randomized, comparator-controlled study using serial FDG PET/CT imaging study of carotid artery and ascending aorta. JACC Cardiovasc Imaging. 2011;4:1110–8.

    PubMed  Article  Google Scholar 

  81. Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. N Engl J Med. 2016;374:1321–31.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events), Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279–1289.

  83. Wanner C, Inzucchi SE, Lachin JM, For the EMPA-REG OUTCOME Investigators, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323–334.

  84. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–22.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. Ojima A, Matsui T, Nishino Y, Nakamura N, Yamagishi S. Empagliflozin, an inhibitor of sodium-glucose cotransporter 2 exerts anti-inflammatory and antifibrotic effects on experimental diabetic nephropathy partly by suppressing AGEs-receptor axis. Horm Metab Res. 2015;47:686–92.

    CAS  PubMed  Article  Google Scholar 

  86. Oelze M, Kröller-Schön S, Welschof P, et al. The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity. PLoS One. 2014;9:e112394.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  87. Inoue T, Inoguchi T, Sonoda N, et al. GLP-1 analog liraglutide protects against cardiac steatosis, oxidative stress and apoptosis in streptozotocin-induced diabetic rats. Atherosclerosis. 2015;240:250–9.

    CAS  PubMed  Article  Google Scholar 

  88. Rizzo M, Abate N, Chandalia M, et al. Liraglutide reduces oxidative stress and restores heme oxygenase-1 and ghrelin levels in patients with type 2 diabetes: a prospective pilot study. J Clin Endocrinol Metab. 2015;100:603–6.

    CAS  PubMed  Article  Google Scholar 

  89. Balestrieri ML, Rizzo MR, Barbieri M, et al. Sirtuin 6 expression and inflammatory activity in diabetic atherosclerotic plaques: effects of incretin treatment. Diabetes. 2015;64:1395–406.

    CAS  PubMed  Article  Google Scholar 

  90. Batchuluun B, Inoguchi T, Sonoda N, et al. Metformin and liraglutide ameliorate high glucose-induced oxidative stress via inhibition of PKC-NAD(P)H oxidase pathway in human aortic endothelial cells. Atherosclerosis. 2014;232:156–64.

    CAS  PubMed  Article  Google Scholar 

  91. Shiraki A, Oyama J, Komoda H, et al. The glucagon-like peptide 1 analog liraglutide reduces TNF-α-induced oxidative stress and inflammation in endothelial cells. Atherosclerosis. 2012;221:375–82.

    CAS  PubMed  Article  Google Scholar 

  92. Shimoda M, Kanda Y, Hamamoto S, et al. The human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells via regulation of cell kinetics and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetes. Diabetologia. 2011;54:1098–108.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247–57.

    CAS  PubMed  Article  Google Scholar 

  94. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327–35.

    CAS  PubMed  Article  Google Scholar 

  95. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317–26.

    CAS  PubMed  Article  Google Scholar 

  96. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232–42.

    CAS  PubMed  Article  Google Scholar 

  97. Smith RJ, Goldfine AB, Hiatt WR. Evaluating the cardiovascular safety of new medications for type 2 diabetes: time to reassess? Diabetes Care. 2016;39:738–42.

    PubMed  Article  Google Scholar 

  98. Elzer JG, Muhammad S, Wintermantel TM, et al. Neuronal estrogen receptor-alpha mediates neuroprotection by 17-beta estradiol. J Cereb Blood Flow Metab. 2010;30:935–42.

    CAS  PubMed  Article  Google Scholar 

  99. Kaunitz AM, Manson JE. Management of menopausal symptoms. Obstet Gynecol. 2015;126:859–76.

    PubMed  PubMed Central  Article  Google Scholar 

  100. Akishita M, Hashimoto M, Ohike Y, et al. Low testosterone level as a predictor of cardiovascular events in Japanese men with coronary risk factors. Atherosclerosis. 2010;210:232–6.

    CAS  PubMed  Article  Google Scholar 

  101. Menke A, Guallar E, Rohrmann S, et al. Sex steroid hormone concentrations and risk of death in US men. Am J Epidemiol. 2010;171:583–92.

    PubMed  Article  Google Scholar 

  102. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310:1353–68.

    CAS  PubMed  Article  Google Scholar 

  103. Schierbeck LL, Rejnmark L, Tofteng CL, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ. 2012;345:e6409.

    PubMed  Article  CAS  Google Scholar 

  104. Hodis HN, Mack WJ, Henderson VW, For the ELITE Research Group, et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 2016;374:1221–1231.

  105. Strehlow K, Rotter S, Wassmann S, et al. Modulation of antioxidant enzyme expression and function by estrogen. Circ Res. 2003;93:170–7.

    CAS  PubMed  Article  Google Scholar 

  106. Song JY, Kim MJ, Jo HH, et al. Antioxidant effect of estrogen on bovine aortic endothelial cells. J Steroid Biochem Mol Biol. 2009;117:74–80.

    CAS  PubMed  Article  Google Scholar 

  107. Haas MJ, Raheja P, Jaimungal S, Sheikh-Ali M, Mooradian AD. Estrogen-dependent inhibition of dextrose-induced endoplasmic reticulum stress and superoxide generation in endothelial cell. Free Radic Biol Med. 2012;52:2161–7.

    CAS  PubMed  Article  Google Scholar 

  108. Mooradian AD. Antioxidant properties of steroids. J Steroid Biochem Mol Biol. 1993;45:509–11.

    CAS  PubMed  Article  Google Scholar 

  109. Duchatelle V, Kritikou EA, Tardif JC. Clinical value of drugs targeting inflammation for the management of coronary artery disease. Can J Cardiol. 2012;28:678–86.

    PubMed  Article  Google Scholar 

  110. Ridker PM, Lüscher TF. Anti-inflammatory therapies for cardiovascular disease. Eur Heart J. 2014;35:1782–91.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. Bäck M, Hansson GK. Anti-inflammatory therapies for atherosclerosis. Nat Rev Cardiol. 2015;12:199–211.

    PubMed  Article  CAS  Google Scholar 

  112. Khan R, Spagnoli V, Tardif JC, L’Allier PL. Novel anti-inflammatory therapies for the treatment of atherosclerosis. Atherosclerosis. 2015;240:497–509.

    CAS  PubMed  Article  Google Scholar 

  113. Adameova A, Xu YJ, Duhamel TA, Tappia PS, Shan L, Dhalla NS. Anti-atherosclerotic molecules targeting oxidative stress and inflammation. Curr Pharm Des. 2009;15:3094–107.

    CAS  PubMed  Article  Google Scholar 

  114. Probst BL, Trevino I, McCauley L, et al. RTA 408, a novel synthetic triterpenoid with broad anticancer and anti-inflammatory activity. PLoS One. 2015;10(4):e0122942.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  115. Chartoumpekis DV, Sykiotis GP. Bardoxolone methyl in type 2 diabetes and advanced chronic kidney disease. N Engl J Med. 2014;370:1767.

    CAS  PubMed  Article  Google Scholar 

  116. Tardif JC, McMurray JJ, Klug E, et al. Effects of succinobucol (AGI-1067) after an acute coronary syndrome: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;371:1761–8.

    CAS  PubMed  Article  Google Scholar 

  117. Tardif JC, Gregoire J, L’Allier PL, et al. Effects of the antioxidant succinobucol (AGI-1067) on human atherosclerosis in a randomized clinical trial. Atherosclerosis. 2008;197:480–6.

    CAS  PubMed  Article  Google Scholar 

  118. Robertson S, Martinez GJ, Payet CA, et al. Colchicine therapy in acute coronary syndrome patients acts on caspase-1 to suppress NLRP3 inflammasome monocyte activation. J Am Heart Assoc. 2015;4:e002128.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  119. Martínez GJ, Robertson S, Barraclough J, et al. Colchicine acutely suppresses local cardiac production of inflammatory cytokines in patients with an acute coronary syndrome. J Am Heart Assoc. 2015;4(8):e002128.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  120. Tousoulis D, Oikonomou E, Economou EK, Crea F, Kaski JC. Inflammatory cytokines in atherosclerosis: current therapeutic approaches. Eur Heart J. 2016;37:1723–32.

    PubMed  Article  Google Scholar 

  121. Perez-Gomez MV, Sanchez-Niño MD, Sanz AB, et al. Horizon 2020 in diabetic kidney disease: the clinical trial pipeline for add-on therapies on top of renin angiotensin system blockade. J Clin Med. 2015;4:1325–47.

    PubMed  PubMed Central  Article  Google Scholar 

  122. Sager HB, Heidt T, Hulsmans M, et al. Targeting interleukin-1β reduces leukocyte production after acute myocardial infarction. Circulation. 2015;132:1880–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J. 2011;162:597–605.

    CAS  PubMed  Article  Google Scholar 

  124. Samuelsson B, Dahlen SE, Lindgren JA, Rouzer CA, Serhan CN. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science. 1987;237:1171–6.

    CAS  PubMed  Article  Google Scholar 

  125. Tardif JC, L’allier PL, Ibrahim R, et al. Treatment with 5-lipoxygenase inhibitor VIA-releuton) in patients with recent acute coronary syndrome. Circ Cardiovasc Imaging. 2010;3:298–307.

    PubMed  Article  Google Scholar 

  126. Gaztanaga J, Farkouh M, Rudd JH, et al. A phase 2 randomized, double-blind, placebo-controlled study of the effect of VIA-2291, a 5-lipoxygenase inhibitor, on vascular inflammation in patients after an acute coronary syndrome. Atherosclerosis. 2015;240:53–60.

    CAS  PubMed  Article  Google Scholar 

  127. Suckling KE. Phospholipase A2 inhibitors in the treatment of atherosclerosis: a new approach moves forward in the clinic. Expert Opin Investig Drugs. 2009;18:1425–30.

    CAS  PubMed  Article  Google Scholar 

  128. Ferri N, Ricci C, Corsini A. Pharmacological inhibition of phosholipase A2: Results from phase 3 clinical trials with darapladib and varespladib in patients with cardiovascular disease. Cardiol Pharmacol. 2015;4:137. doi:10.4172/2329-6607.1000137.

    Google Scholar 

  129. Nicholls SJ, Kastelein JJ, Schwartz GG, Bash D, Rosenson RS, et al. Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial. JAMA. 2014;311:252–62.

    CAS  PubMed  Article  Google Scholar 

  130. STABILITY Investigators, White HD, Held C, Stewart R, et al. Darapladib for preventing ischemic events in stable coronary heart disease. N Engl J Med. 2014;370:1702–1711.

  131. O’Donoghue ML, Braunwald E, White HD, et al. Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. JAMA. 2014;312:1006–15.

    PubMed  Article  CAS  Google Scholar 

  132. Tardif JC, Tanguay JF, Wright SS, et al. Effects of the P-selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention for non-ST-segment elevation myocardial infarction: results of the SELECT-ACS trial. J Am Coll Cardiol. 2013;61:2048–55.

    CAS  PubMed  Article  Google Scholar 

  133. Stähli BE, Tardif JC, Carrier M, et al. Effects of P-selectin antagonist inclacumab in patients undergoing coronary artery bypass graft surgery: SELECT-CABG Trial. J Am Coll Cardiol. 2016;67:344–6.

    PubMed  Article  CAS  Google Scholar 

  134. Tardif JC, L’Allier PL, Grégoire J, et al. A randomized controlled, phase 2 trial of the viral serpin Serp-1 in patients with acute coronary syndromes undergoing percutaneous coronary intervention. Circ Cardiovasc Interv. 2010;3:543–8.

    CAS  PubMed  Article  Google Scholar 

  135. Rouch A, Vanucci-Bacqué C, Bedos-Belval F, Baltas M. Small molecules inhibitors of plasminogen activator inhibitor-1 - an overview. Eur J Med Chem. 2015;92:619–36.

    CAS  PubMed  Article  Google Scholar 

  136. Blot WJ, Li JY, Taylor PR, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease specific mortality in the general population. J Natl Cancer Inst. 1993;85:1483–92.

    CAS  PubMed  Article  Google Scholar 

  137. ATBC (Alpha-Tocopherol, Beta Carotene) Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. 1994;330:1029–1035.

  138. Stephens NG, Parsons A, Schofield PM, et al. Randomized, controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study. Lancet. 1996;347:781–6.

    CAS  PubMed  Article  Google Scholar 

  139. Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med. 1996;334:1145–9.

    CAS  PubMed  Article  Google Scholar 

  140. Omenn GS, Goodman GE, Thornquist MD, et al. Risk factors for lung cancer and for intervention effects in CARET: the Beta Carotene and Retinol Efficacy Trial. J Natl Cancer Inst. 1996;88:1550–9.

    CAS  PubMed  Article  Google Scholar 

  141. GISSI-Prevenzione Investigators. Dietary supplements with n-3 poly unsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevention Trial. Lancet. 1999;354:447–455.

  142. Yusuf S, Dagenais G, Pogue J, et al. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:154–60.

    CAS  PubMed  Article  Google Scholar 

  143. Collaborative Group of the Primary Prevention Project. Low dose aspirin and vitamin E in people at cardiovascular risk: a randomized trial in general practice. Lancet. 2001;357:89–95.

    Article  Google Scholar 

  144. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:23–33.

    Article  Google Scholar 

  145. Lee IM, Cook NR, Gaziano JM, et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial. JAMA. 2005;294:56–65.

    CAS  PubMed  Article  Google Scholar 

  146. Cook NR, Albert CM, Gaziano JM, et al. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women’s Antioxidant Cardiovascular Study. Arch Intern Med. 2007;167:1610–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. Sesso HD, Buring JE, Christen WG, et al. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2008;300:2123–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. Sheikh-Ali M, Chehade JM, Mooradian AD. The antioxidant paradox in diabetes mellitus. Am J Ther. 2011;18:266–78.

    PubMed  Article  Google Scholar 

  149. Mooradian AD, Haas MJ. Glucose-induced endoplasmic reticulum stress is independent of oxidative stress: a mechanistic explanation for the failure of antioxidant therapy in diabetes. Free Radic Biol Med. 2011;50:1140–3.

    CAS  PubMed  Article  Google Scholar 

  150. Mooradian AD, Onstead-Haas L, Haas MJ. Asymmetrical cross-talk between the endoplasmic reticulum stress and oxidative stress caused by dextrose. Life Sci. 2016;144:37–48.

    CAS  PubMed  Article  Google Scholar 

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Mooradian, A.D. Therapeutic Targeting of Cellular Stress to Prevent Cardiovascular Disease: A Review of the Evidence. Am J Cardiovasc Drugs 17, 83–95 (2017). https://doi.org/10.1007/s40256-016-0199-7

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Keywords

  • Metformin
  • Endoplasmic Reticulum Stress
  • Ezetimibe
  • Liraglutide
  • Aliskiren