Omega-3 Fatty Acid Modifies Serum HSP 70 and hs-CRP in Patients With Cardiovascular Disease: Randomized Double‐Blind Placebo-Controlled Trial

  • Simin Samavat Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran.
  • Mahmoud Djalali Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran.
  • Ebrahim Nematipour Department of Cardiology, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran.
  • Mohammad Reza Eshraghian Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
  • Mahnaz Zarei Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran.
  • Sanaz Gholamhoseini Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran.
  • Mohammad Hassan Javanbakht Mail Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran.
HSP-70, hsCRP, Cardiovascular disease, Omega-3 fatty acid


All stages of initiation and progression of atherosclerosis are associated with inflammatory responses. Heat shock proteins (HSP-70) can play an important role in the pathogenesis of atherosclerosis. Serum High-sensitivity C-reactive protein (hs-CRP) is significantly associated with the severity of coronary arteriosclerosis. Omega 3 fatty acids contribute to the primary and secondary prevention of cardiovascular disease (CVD). The purpose of the current study was to assess the effect of omega-3 on serum HSP-70 and HsCRP in patients with atherosclerosis. The current study was a randomized, placebo-controlled, double-blind parallel-group clinical trial, involving 42 male patients with coronary artery disease (CAD). The volunteers were randomly allocated into two groups to receive 4 g omega-3 (containing 720 mg EPA plus 480 mg DHA) supplements (n=21) or placebo (n=21) per day for 8 weeks. Fasting blood samples were taken at the beginning and end of the trial to quantify serum levels of HSP-70 and hsCRP concentrations. The result of the present study revealed that no significant difference was observed between two groups before and after the intervention in terms of serum levels of Cholesterol, Triglyceride, FBS, serum Insulin and homeostasis model of assessment-insulin resistance (HOMA-IR). The difference of HSP-70 between two groups was statistically significant (P=0.04). There was no significant difference between two groups for hsCRP. The study showed that taking omega-3 fatty acids can ameliorate serum HSP-70 as inflammatory parameters. The results suggest more investigation to assess the pathway omega-3 leads to lower incidence of CVD.


Napoli C, D'armiento F, Mancini F, Postiglione A, Witztum J, Palumbo G, et al. Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J Clin Invest 1997;100:2680-90.

Epstein FH, Ross R. Atherosclerosisan inflammatory disease. N Engl J Med 1999;340:115-26.

Wick G, Kleindienst R, Schett G, Amberger A, Xu Q. Role of heat shock protein 65/60 in the pathogenesis of atherosclerosis. Int Arch Allergy Immunol 1995;107:130-1.

Pockley AG. Heat shock proteins, inflammation, and cardiovascular disease. Circulation 2002;105:1012-7.

Wick G, Knoflach M, Xu Q. Autoimmune and inflammatory mechanisms in atherosclerosis. Annu Rev Immunol 2004;22:361-403.

Hu Z, Yang B, Lu W, Zhou W, Zeng L, Li T, et al. HSPB2/MKBP, a novel and unique member of the small heat‐shock protein family. J Neurosci Res 2008;86:2125-33.

Lamb DJ, El-Sankary W, Ferns GA. Molecular mimicry in atherosclerosis: a role for heat shock proteins in immunisation. Atherosclerosis 2003;167:177-85.

Xu Q. Role of heat shock proteins in atherosclerosis. Arterioscler Thromb Vasc Biol 2002;22:1547-59.

Bruce CR, Carey AL, Hawley JA, Febbraio MA. Intramuscular Heat Shock Protein 72 and Heme Oxygenase-1 mRNA Are Reduced in Patients With Type 2 Diabetes Evidence That Insulin Resistance Is Associated With a Disturbed Antioxidant Defense Mechanism. Diabetes 2003;52:2338-45.

House S, Guidon Jr P, Perdrizet G, Rewinski M, Kyriakos R, Bockman R, et al. Effects of heat shock, stannous chloride, and gallium nitrate on the rat inflammatory response. Cell Stress Chaperones 2001;6:164-71.

Zhang X, Xu Z, Zhou L, Chen Y, He M, Cheng L, et al. Plasma levels of Hsp70 and anti-Hsp70 antibody predict risk of acute coronary syndrome. Cell Stress Chaperones 2010;15:675-86.

Leng X, Wang X, Pang W, Zhan R, Zhang Z, Wang L, et al. Evidence of a role for both anti-Hsp70 antibody and endothelial surface membrane Hsp70 in atherosclerosis. Cell Stress Chaperones 2013;18:483-93.

Bobryshev YV, Lord RS. Expression of heat shock protein–70 by dendritic cells in the arterial intima and its potential significance in atherogenesis. J Vasc Surg 2002;35:368-75.

Blake GJ, Ridker PM. C-reactive protein and other inflammatory risk markers in acute coronary syndromes. J Am Coll Cardiol 2003;41:S37-42.

Ridker PM, Bassuk SS, Toth PP. C-reactive protein and risk of cardiovascular disease: evidence and clinical application. Curr Atheroscler Rep 2003;5:341-9.

Wang C, Harris WS, Chung M, Lichtenstein AH, Balk EM, Kupelnick B, et al. n-3 Fatty acids from fish or fish-oil supplements, but not α-linolenic acid, benefit cardiovascular disease outcomes in primary-and secondary-prevention studies: a systematic review. Am J Clin Nutr 2006;84:5-17.

Ferrucci L, Cherubini A, Bandinelli S, Bartali B, Corsi A, Lauretani F, et al. Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers. J Clin Endocrinol Metab 2006;91:439-46.

Organization WH. Waist Circumference and Waist-Hip Ratio Report of a WHO Expert Consultation. (Accessed May 2018, 22, at

Hightower LE, Guidon PT. Selective release from cultured mammalian cells of heat‐shock (stress) proteins that resemble glia‐axon transfer proteins. J Cell Physiol 1989;138:257-66.

Asea A. Stress proteins and initiation of immune response: chaperokine activity of hsp72. Exerc Immunol Rev 2005;11:34.

Tytell M, Greenberg S, Lasek R. Heat shock-like protein is from glia to axon. Brain Res 1986;363:161-4.

Krepuska M, Szeberin Z, Sótonyi P, Sarkadi H, Fehérvári M, Apor A, et al. Serum level of soluble Hsp70 is associated with vascular calcification. Cell Stress Chaperones 2011;16:257-65.

Chan Y, Shukla N, Abdus-Samee M, Berwanger C, Stanford J, Singh M, et al. Anti-heat-shock protein 70 kDa antibodies in vascular patients. Eur J Vasc Endovasc Surg 1999;18:381-5.

Wright BH, Corton JM, El-Nahas AM, Wood RF, Pockley AG. Elevated levels of circulating heat shock protein 70 (Hsp70) in peripheral and renal vascular disease. Heart Vessels 2000;15:18-22.

Genth-Zotz S, Bolger AP, Kalra PR, von Haehling S, Doehner W, Coats AJ, et al. Heat shock protein 70 in patients with chronic heart failure: relation to disease severity and survival. Int J Cardiol 2004;96:397-401.

Dybdahl B, Slørdahl S, Waage A, Kierulf P, Espevik T, Sundan A. Myocardial ischaemia and the inflammatory response: release of heat shock protein 70 after myocardial infarction. Heart 2005;91:299-304.

Madden J, Coward JC, Shearman CP, Grimble RF, Calder PC. Hsp70 expression in monocytes from patients with peripheral arterial disease and healthy controls. Cell Biol Toxicol 2010;26:215-23.

Martin-Ventura JL, Leclercq A, Blanco-Colio LM, Egido J, Rossignol P, Meilhac O, et al. Low plasma levels of HSP70 in patients with carotid atherosclerosis are associated with increased levels of proteolytic markers of neutrophil activation. Atherosclerosis 2007;194:334-41.

Bielecka-Dabrowa A, Barylski M, Mikhailidis DP, Rysz J, Banach M. HSP 70 and atherosclerosis-protector or activator? Expert Opin Ther Targets 2009;13:307-17.

Johnson AD, Berberian PA, Bond MG. Effect of heat shock proteins on survival of isolated aortic cells from normal and atherosclerotic cynomolgus macaques. Atherosclerosis 1990;84:111-9.

Volloch V, Gabai VL, Rits S, Force T, Sherman MY. HSP72 can protect cells from heat-induced apoptosis by accelerating the inactivation of stress kinase JNK. Cell Stress Chaperones 2000;5:139-47.

Svensson P-A, Asea A, Englund MC, Bausero MA, Jernås M, Wiklund O, et al. Major role of HSP70 as a paracrine inducer of cytokine production in human oxidized LDL treated macrophages. Atherosclerosis 2006;185:32-8.

Asea A, Kraeft S-K, Kurt-Jones EA, Stevenson MA, Chen

LB, Finberg RW, et al. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 2000;6:435-42.

Mandal K, Jahangiri M, Xu Q. Autoimmunity to heat shock proteins in atherosclerosis. Autoimmun Rev 2004;3:31-7.

Zheng JL, Lu L, Hu J, Zhang RY, Zhang Q, Chen QJ, et al. Increased serum YKL-40 and C-reactive protein levels are associated with angiographic lesion progression in patients with coronary artery disease. Atherosclerosis 2010;210:590-5.

Hashimoto H, Kitagawa K, Hougaku H, Shimizu Y, Sakaguchi M, Nagai Y, et al. C-reactive protein is an independent predictor of the rate of increase in early carotid atherosclerosis. Circulation 2001;104:63-7.

Piranfar MA. The correlation between high-sensitivity C-reactive protein (HSCRP) serum levels and severity of coronary atherosclerosis. Int Cardiovasc Res J 2014;8:6-8.

Li L, Roumeliotis N, Sawamura T, Renier G. C-Reactive Protein Enhances LOX-1 Expression in Human Aortic Endothelial Cells Relevance of LOX-1 to C-Reactive Protein–Induced Endothelial Dysfunction. Circ Res 2004;95:877-83.

Micallef M, Munro I, Garg M. An inverse relationship between plasma n-3 fatty acids and C-reactive protein in healthy individuals. Eur J Clin Nutr 2009;63:1154-6.

Niknam M, Paknahad Z, Maracy MR, Hashemi M. Dietary fatty acids and inflammatory markers in patients with coronary artery disease. Adv Biomed Res 2014;3:148.

Saifullah A, Watkins BA, Saha C, Li Y, Moe SM, Friedman AN. Oral fish oil supplementation raises blood omega-3 levels and lowers C-reactive protein in haemodialysis patients—a pilot study. Nephrol Dial Transplant 2007;22:3561-7.

Kantor ED, Lampe JW, Vaughan TL, Peters U, Rehm CD, White E. Association between use of specialty dietary supplements and C-reactive protein concentrations. Am J Epidemiol 2012;176:1002-13.

Kantor ED. Use of glucosamine, chondroitin, and omega-3 fatty acid supplements in relation to inflammation and risk of colorectal cancer: University of Washington; 2012. (Accessed May 2018, 22:at

How to Cite
Samavat S, Djalali M, Nematipour E, Eshraghian MR, Zarei M, Gholamhoseini S, Javanbakht MH. Omega-3 Fatty Acid Modifies Serum HSP 70 and hs-CRP in Patients With Cardiovascular Disease: Randomized Double‐Blind Placebo-Controlled Trial. Acta Med Iran. 56(6):379-385.