Abstract
Atherosclerosis is an inflammatory disease, but the respone of the endogenous anti-inflammatory
system during this process has not been evaluated previously. Cortisol is the end
product of this anti-inflammatory system, but is also able to activate cellular processes
that induce atherogenesis; however, it is unknown whether atherogenesis occurs when
circulating concentrations of endogenous cortisol are increased or when they are decreased.
We have evaluated the counter-regulatory responses of cortisol and interleukin-1β
(IL-1β) during the short- and long-term responses to vascular injury in rabbits fed
a 2% cholesterol diet. In the short-term group (n = 18), serum cortisol and IL-1β concentrations were measured after 10, 20 and 30 days.
Rabbits developed hypercholesterolemia and hypercortisolemia, with only modest increases
in IL-1β. Although inflammation was low-grade, atherogenesis took place, with subintimal
lipid accumulation evident on day 30. In the second group (n = 18), we evaluated variables after 40, 60 and 90 days. This group developed hypercholesterolemia,
but serum cortisol concentrations were inappropriately normal, while IL-1β concentrations
were elevated 8.6-fold; advanced atherosclerotic plaques were evident on days 60 and
90. These results show that atherogenesis occurs when high endogenous cortisol levels
are suppressing inflammation, and are consistent with a promotion of early atherogenesis
by high cortisol concentrations.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to AtherosclerosisAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Atherosclerosis: an inflammatory disease.N Engl J Med. 1999; 340: 115-126
- Inflammation in atherosclerosis.Nature. 2002; 420: 868-874
- Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime.Nat Med. 2002; 8: 1211-1217
- Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: effects of an early invasive or noninvasive strategy.J Am Med Assoc. 2001; 286: 2107-2113
- Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men.Circulation. 2000; 101: 1767-1772
- C-reactive protein and coronary heart disease.N Engl J Med. 2004; 350: 1387-1397
- Estrogens and glucocorticoids inhibit endothelial vascular cell adhesion molecule-1 expression by different transcriptional mechanisms.Circ Res. 2000; 87: 19-25
- Regulation of monocyte CD36 and thrombospondin-1 expression by soluble mediators.Arterioscler Thromb Vasc Biol. 1996; 16: 1019-1025
- Synthetic glucocorticoids that dissociate transactivation and AP-1 transrepression exhibit antiinflammatory activity in vivo.Mol Endocrinol. 1997; 11: 1245-1255
- Nuclear hormone receptor antagonism with AP-1 by inhibition of the JNK pathway.Genes Dev. 1997; 11: 3351-3364
- MIF as glucocorticoid-induced modulator of cytokine production.Nature. 1995; 377: 68-71
- Macrophage migration inhibitory factor is a critical mediator of the activation of immune cells by exotoxins of Gram-positive bacteria.Proc Natl Acad Sci USA. 1998; 95: 11383-11388
- Macrophage migration inhibitory factor: molecular, cellular and genetic aspects of a key neuroendocrine molecule.J Endocrinol. 2004; 182: 1-9
- Donnely SC Macrophage migration inhibitory factor: a neuroendocrine modulator of chronic inflammation.J Endocrinol. 2003; 179: 15-23
- Regulation of macrophage migration inhibitory factor expression by glucocorticoids in vivo.Am J Pathol. 2003; 162: 47-56
- De novo expression of macrophage migration inhibitory factor in atherogenesis in rabbits.Circ Res. 2000; 87: 1202-1208
- Stabilization of atherosclerotic plaques by blockade of macrophage migration inhibitory factor after vascular injury in apolipoprotein E-deficient mice.Circulation. 2004; 109: 380-385
- Macrophage migration inhibitory factor deficiency impairs atherosclerosis in low-density lipoprotein receptor-deficient mice.Circulation. 2004; 109: 3149-3153
- Evidence for vascular macrophage migration inhibitory factor in destabilization of human atherosclerotic plaques.Cardiovsc Res. 2005; 65: 272-282
- Expression of macrophage migration inhibitory factor in different stages of human atherosclerosis.Circulation. 2002; 105: 1561-1566
- Cushing's syndrome—killing disease: discriminatory value of signs and symptoms aiding early diagnosis.Lancet. 1982; 2: 646-649
- Effect of glucocorticoids on the arteries in rheumatoid arthritis.Arthritis Rheum. 2004; 50: 3813-3822
- Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy.Circulation. 1999; 99: 2192-2217
- Molecular and cellular interface between behavior and acute coronary syndromes.Cardiovasc Res. 2002; 56: 15-21
- The role of stress and the hypothalamic–pituitary–adrenal axis in the pathogenesis of the metabolic syndrome: neuro-endocrine and target tissue-related causes.Int J Obes Relat Metab Disord. 2000; 24: S50-S55
- Behavioral and emotional triggers of acute coronary syndromes: a systematic review and critique.Psychosom Med. 2005; 67: 79-186
- The hypothalamic–pituitary–adrenal axis and immune-mediated inflammation.N Engl J Med. 1995; 332: 1351-1362
- Protective and damaging effects of stress mediators.N Engl J Med. 1998; 338: 171-179
- Does altered glucocorticoid homeostasis increase cardiovascular risk?.Cardiovasc Res. 2004; 64: 217-226
- Circulating levels of glucocorticoid hormones in WHHL and NZW rabbits: circadian cycle and response to repeated social encounter.Psychoneuroendocrinology. 2004; 29: 861-866
- Low-grade systemic inflammation impairs arterial stiffness in newly diagnosed hypercholesterolaemia.Eur J Clin Invest. 2004; 34: 335-341
- Morning cortisol production in coronary heart disease patients.Eur J Clin Invest. 2002; 32: 304-308
- Individual reactivity and physiology of the stress response.Biomed Pharmacother. 2000; 54: 122-128
- 11Beta-hydroxysteroid dehydrogenase type 1: a tissue-specific amplifier of glucocorticoid action.Endocrinology. 2001; 142: 1371-1376
- Selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice.Diabetologia. 2002; 45: 1528-1532
- Effects of the 11 beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with type 2 diabetes.J Clin Endocrinol Metab. 2003; 88: 285-291
Article info
Publication history
Published online: June 28, 2006
Accepted:
May 24,
2006
Received in revised form:
May 18,
2006
Received:
March 3,
2006
Identification
Copyright
© 2006 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
