The effect of salsalate therapy on endothelial function in a broad range of subjects

Anju Nohria, Scott Kinlay, J Stewart Buck, Whitney Redline, Robert Copeland-Halperin, Sora Kim, Joshua A Beckman, Anju Nohria, Scott Kinlay, J Stewart Buck, Whitney Redline, Robert Copeland-Halperin, Sora Kim, Joshua A Beckman

Abstract

Background: Inflammation is fundamental to the development of atherosclerosis. We examined the effect of anti-inflammatory doses of salicylate on endothelium-dependent vasodilation, a biomarker of cardiovascular risk, in a broad range of subjects.

Methods and results: We performed a randomized, double-blind, placebo-controlled crossover trial evaluating the effects of 4 weeks of high-dose salsalate (disalicylate) therapy on endothelium-dependent flow-mediated and endothelium-independent vasodilation. Fifty-eight subjects, including 17 with metabolic syndrome, 13 with atherosclerosis, and 28 healthy controls, were studied. Among all subjects, endothelium-dependent flow-mediated vasodilation decreased after salsalate compared with placebo therapy (P=0.01), whereas nitroglycerin-mediated, endothelium-independent vasodilation was unchanged (P=0.97). Endothelium-dependent flow-mediated vasodilation after salsalate therapy was impaired compared with placebo therapy in subjects with therapeutic salicylate levels (n=31, P<0.02) but not in subjects with subtherapeutic levels (P>0.2).

Conclusions: Salsalate therapy, particularly when therapeutic salicylate levels are achieved, impairs endothelium-dependent vasodilation in a broad range of subjects. These data raise concern about the possible deleterious effects of anti-inflammatory doses of salsalate on cardiovascular risk.

Clinical trial registration url: www.clinicaltrials.gov. Unique Identifiers: NCT00760019 and NCT00762827.

Keywords: atherosclerosis; endothelium; glucose; inflammation; vasodilation.

Figures

Figure 1.
Figure 1.
Flow‐mediated, endothelium‐dependent vasodilation of the brachial artery after placebo (P) and salsalate (S) therapy. Data shown are median (IQR). ATHERO indicates atherosclerosis; MET, metabolic syndrome.
Figure 2.
Figure 2.
Nitroglycerin‐mediated, endothelium‐independent vasodilation of the brachial artery after placebo (P) and salsalate (S) therapy. Data shown are median (IQR). ATHERO indicates atherosclerosis; MET, metabolic syndrome.
Figure 3.
Figure 3.
Flow‐mediated, endothelium‐dependent vasodilation of the brachial artery after placebo (P) and salsalate (S) therapy in subjects with a therapeutic salicylate level and those with a subtherapeutic level. Data shown are median (IQR).

References

    1. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002; 105:1135-1143
    1. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ. Rosuvastatin to prevent vascular events in men and women with elevated C‐reactive protein. N Engl J Med. 2008; 359:2195-2207
    1. Ridker PM. Testing the inflammatory hypothesis of atherothrombosis: scientific rationale for the Cardiovascular Inflammation Reduction Trial (CIRT). J Thromb Haemost. 2009; 7suppl 1:332-339
    1. 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
    1. Liao F, Andalibi A, Qiao JH, Allayee H, Fogelman AM, Lusis AJ. Genetic evidence for a common pathway mediating oxidative stress, inflammatory gene induction, and aortic fatty streak formation in mice. J Clin Invest. 1994; 94:877-884
    1. Chiba T, Kondo Y, Shinozaki S, Kaneko E, Ishigami A, Maruyama N, Umezawa K, Shimokado K. A selective NFkappaB inhibitor, DHMEQ, reduced atherosclerosis in apoE‐deficient mice. J Atheroscler Thromb. 2006; 13:308-313
    1. Gareus R, Kotsaki E, Xanthoulea S, van der Made I, Gijbels MJ, Kardakaris R, Polykratis A, Kollias G, de Winther MP, Pasparakis M. Endothelial cell‐specific NF‐kappaB inhibition protects mice from atherosclerosis. Cell Metab. 2008; 8:372-383
    1. Hasegawa Y, Saito T, Ogihara T, Ishigaki Y, Yamada T, Imai J, Uno K, Gao J, Kaneko K, Shimosawa T, Asano T, Fujita T, Oka Y, Katagiri H. Blockade of the nuclear factor‐kappaB pathway in the endothelium prevents insulin resistance and prolongs life spans. Circulation. 2012; 125:1122-1133
    1. Frantz B, O'Neill EA. The effect of sodium salicylate and aspirin on NF‐kappaB. Science. 1995; 270:2017-2019
    1. Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, Ye J. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem. 2002; 277:48115-48121
    1. Kim JK, Kim YJ, Fillmore JJ, Chen Y, Moore I, Lee J, Yuan M, Li ZW, Karin M, Perret P, Shoelson SE, Shulman GI. Prevention of fat‐induced insulin resistance by salicylate. J Clin Invest. 2001; 108:437-446
    1. Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE. Local and systemic insulin resistance resulting from hepatic activation of IKK‐beta and NF‐kappaB. Nat Med. 2005; 11:183-190
    1. Goldfine AB, Fonseca V, Jablonski KA, Pyle L, Staten MA, Shoelson SE. The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial. Ann Intern Med. 2010; 152:346-357
    1. Goldfine AB, Silver R, Aldhahi W, Cai D, Tatro E, Lee J, Shoelson SE. Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. Clin Transl Sci. 2008; 1:36-43
    1. Kim F, Tysseling KA, Rice J, Gallis B, Haji L, Giachelli CM, Raines EW, Corson MA, Schwartz MW. Activation of IKKbeta by glucose is necessary and sufficient to impair insulin signaling and nitric oxide production in endothelial cells. J Mol Cell Cardiol. 2005; 39:327-334
    1. Kim F, Tysseling KA, Rice J, Pham M, Haji L, Gallis BM, Baas AS, Paramsothy P, Giachelli CM, Corson MA, Raines EW. Free fatty acid impairment of nitric oxide production in endothelial cells is mediated by IKKbeta. Arterioscler Thromb Vasc Biol. 2005; 25:989-994
    1. Fleischman A, Shoelson SE, Bernier R, Goldfine AB. Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care. 2008; 31:289-294
    1. Goldfine AB, Fonseca V, Jablonski KA, Chen YD, Tipton L, Staten MA, Shoelson SE. Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial. Ann Intern Med. 2013; 159:1-12
    1. Beckman JA, Liao JK, Hurley S, Garrett LA, Chui D, Mitra D, Creager MA. Atorvastatin restores endothelial function in normocholesterolemic smokers independent of changes in low‐density lipoprotein. Circ Res. 2004; 95:217-223
    1. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard‐Herman M, Herrington D, Vallance P, Vita J, Vogel R. Guidelines for the ultrasound assessment of endothelial‐dependent flow‐mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002; 39:257-265
    1. Burry HC, Dieppe PA. Apparent reduction of endogenous creatinine clearance by salicylate treatment. Br Med J. 1976; 2:16-17
    1. Morris HG, Sherman NA, McQuain C, Goldlust MB, Chang SF, Harrison LI. Effects of salsalate (nonacetylated salicylate) and aspirin on serum prostaglandins in humans. Ther Drug Monit. 1985; 7:435-438
    1. Lieberman EH, Gerhard MD, Uehata A, Selwyn AP, Ganz P, Yeung AC, Creager MA. Flow‐induced vasodilation of the human brachial artery is impaired in patients <40 years of age with coronary artery disease. Am J Cardiol. 1996; 78:1210-1214
    1. Mitchell JA, Saunders M, Barnes PJ, Newton R, Belvisi MG. Sodium salicylate inhibits cyclo‐oxygenase‐2 activity independently of transcription factor (nuclear factor kappaB) activation: role of arachidonic acid. Mol Pharmacol. 1997; 51:907-912
    1. Verma S, Raj SR, Shewchuk L, Mather KJ, Anderson TJ. Cyclooxygenase‐2 blockade does not impair endothelial vasodilator function in healthy volunteers: randomized evaluation of rofecoxib versus naproxen on endothelium‐dependent vasodilatation. Circulation. 2001; 104:2879-2882
    1. Bogaty P, Brophy JM, Noel M, Boyer L, Simard S, Bertrand F, Dagenais GR. Impact of prolonged cyclooxygenase‐2 inhibition on inflammatory markers and endothelial function in patients with ischemic heart disease and raised C‐reactive protein: a randomized placebo‐controlled study. Circulation. 2004; 110:934-939
    1. Florez A, de Haro J, Martinez E, Varela C, Bleda S, Acin F. Selective cyclooxygenase‐2 inhibition reduces endothelial dysfunction and improves inflammatory status in patients with intermittent claudication. Rev Esp Cardiol. 2009; 62:851-857
    1. Pierce GL, Lesniewski LA, Lawson BR, Beske SD, Seals DR. Nuclear factor‐{kappa}b activation contributes to vascular endothelial dysfunction via oxidative stress in overweight/obese middle‐aged and older humans. Circulation. 2009; 119:1284-1292
    1. Gupta SK, Johnson RM, Saha C, Mather KJ, Greenwald ML, Waltz JS, Rehman J, Dube MP. Improvement in HIV‐related endothelial dysfunction using the anti‐inflammatory agent salsalate: a pilot study. AIDS. 2008; 22:653-655
    1. Hileman CO, Carman TL, Gripshover BM, O'Riordan M, Storer NJ, Harrill DE, White CA, McComsey GA. Salsalate is poorly tolerated and fails to improve endothelial function in virologically suppressed HIV‐infected adults. AIDS. 2010; 24:1958-1961
    1. Tabit CE, Holbrook M, Shenouda SM, Dohadwala MM, Widlansky ME, Frame AA, Kim BH, Duess MA, Kluge MA, Levit A, Keaney JF, Jr, Vita JA, Hamburg NM. Effect of sulfasalazine on inflammation and endothelial function in patients with established coronary artery disease. Vasc Med. 2012; 17:101-107
    1. Goldfine AB, Conlin PR, Halperin F, Koska J, Permana P, Schwenke D, Shoelson SE, Reaven PD. A randomised trial of salsalate for insulin resistance and cardiovascular risk factors in persons with abnormal glucose tolerance. Diabetologia. 2013; 56:714-723
    1. Arcaro G, Zenere BM, Saggiani F, Zenti MG, Monauni T, Lechi A, Muggeo M, Bonadonna RC. Ace inhibitors improve endothelial function in type 1 diabetic patients with normal arterial pressure and microalbuminuria. Diabetes Care. 1999; 22:1536-1542
    1. Mayer EL, Dallabrida SM, Rupnick MA, Redline WM, Hannagan K, Ismail NS, Burstein HJ, Beckman JA. Contrary effects of the receptor tyrosine kinase inhibitor vandetanib on constitutive and flow‐stimulated nitric oxide elaboration in humans. Hypertension. 2011; 58:85-92
    1. Chu TF, Rupnick MA, Kerkela R, Dallabrida SM, Zurakowski D, Nguyen L, Woulfe K, Pravda E, Cassiola F, Desai J, George S, Morgan JA, Harris DM, Ismail NS, Chen JH, Schoen FJ, Van den Abbeele AD, Demetri GD, Force T, Chen MH. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet. 2007; 370:2011-2019
    1. Giugliano D, Sacca L, Scognamiglio G, Ungaro B, Torella R. Influence of acetylsalicylic acid on glucose turnover in normal man. Diabetes Metab. 1982; 8:279-282
    1. Newman WP, Brodows RG. Aspirin causes tissue insensitivity to insulin in normal man. J Clin Endocrinol Metab. 1983; 57:1102-1106
    1. Hundal RS, Petersen KF, Mayerson AB, Randhawa PS, Inzucchi S, Shoelson SE, Shulman GI. Mechanism by which high‐dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Invest. 2002; 109:1321-1326
    1. Faghihimani E, Aminorroaya A, Rezvanian H, Adibi P, Ismail‐Beigi F, Amini M. Salsalate reduces insulin resistance and plasma glucose level in persons with prediabetes. Endocr Pract. 2012:1-17
    1. Meex RC, Phielix E, Moonen‐Kornips E, Schrauwen P, Hesselink MK. Stimulation of human whole‐body energy expenditure by salsalate is fueled by higher lipid oxidation under fasting conditions and by higher oxidative glucose disposal under insulin‐stimulated conditions. J Clin Endocrinol Metab. 2011; 96:1415-1423
    1. Chai W, Liu J, Jahn LA, Fowler DE, Barrett EJ, Liu Z. Salsalate attenuates free fatty acid‐induced microvascular and metabolic insulin resistance in humans. Diabetes Care. 2011; 34:1634-1638
    1. Koska J, Ortega E, Bunt JC, Gasser A, Impson J, Hanson RL, Forbes J, de Courten B, Krakoff J. The effect of salsalate on insulin action and glucose tolerance in obese non‐diabetic patients: results of a randomised double‐blind placebo‐controlled study. Diabetologia. 2009; 52:385-393
    1. Carlson LA, Osiman J. Effect of sancylates on plasmafree fatty acid in normal and diabetic subjects. Metabolism. 1961; 10:781-787
    1. Bizzi A, Codegoni AM, Garattini S. Salicylate, a powerful inhibitor of free fatty acid release. Nature. 1964; 204:1205.
    1. Zu L, Jiang H, He J, Xu C, Pu S, Liu M, Xu G. Salicylate blocks lipolytic actions of tumor necrosis factor‐alpha in primary rat adipocytes. Mol Pharmacol. 2008; 73:215-223
    1. Bajaj M, Suraamornkul S, Romanelli A, Cline GW, Mandarino LJ, Shulman GI, DeFronzo RA. Effect of a sustained reduction in plasma free fatty acid concentration on intramuscular long‐chain fatty acyl‐CoAs and insulin action in type 2 diabetic patients. Diabetes. 2005; 54:3148-3153
    1. van Diepen JA, Wong MC, Guigas B, Bos J, Stienstra R, Hodson L, Shoelson SE, Berbee JF, Rensen PC, Romijn JA, Havekes LM, Voshol PJ. Hepatocyte‐specific IKK‐beta activation enhances VLDL‐triglyceride production in ApoE*3‐Leiden mice. J Lipid Res. 2011; 52:942-950
    1. Clapp BR, Hingorani AD, Kharbanda RK, Mohamed‐Ali V, Stephens JW, Vallance P, MacAllister RJ. Inflammation‐induced endothelial dysfunction involves reduced nitric oxide bioavailability and increased oxidant stress. Cardiovasc Res. 2004; 64:172-178
    1. Yin MJ, Yamamoto Y, Gaynor RB. The anti‐inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)b kinase‐beta. Nature. 1998; 396:77-80
    1. Schwenger P, Alpert D, Skolnik EY, Vilcek J. Activation of p38 mitogen‐activated protein kinase by sodium salicylate leads to inhibition of tumor necrosis factor‐induced IkappaB alpha phosphorylation and degradation. Mol Cell Biol. 1998; 18:78-84
    1. Cronstein BN, Montesinos MC, Weissmann G. Salicylates and sulfasalazine, but not glucocorticoids, inhibit leukocyte accumulation by an adenosine‐dependent mechanism that is independent of inhibition of prostaglandin synthesis and p105 of NFkappaB. Proc Natl Acad Sci USA. 1999; 96:6377-6381
    1. Xu XM, Sansores‐Garcia L, Chen XM, Matijevic‐Aleksic N, Du M, Wu KK. Suppression of inducible cyclooxygenase 2 gene transcription by aspirin and sodium salicylate. Proc Natl Acad Sci USA. 1999; 96:5292-5297
    1. Tabit CE, Holbrook M, Shenouda SM, Dohadwala MM, Widlansky ME, Frame AA, Kim BH, Duess MA, Kluge MA, Levit A, Keaney JF, Jr, Vita JA, Hamburg NM. Effect of sulfasalazine on inflammation and endothelial function in patients with established coronary artery disease. Vasc Med. 2012; 17:101-107

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe