Social status, environment, and atherosclerosis in cynomolgus monkeys. Arteriosclerosis 2:359-368

Arteriosclerosis (Dallas, Tex.) 09/1982; 2(5):359-68. DOI: 10.1161/01.ATV.2.5.359
Source: PubMed


The purpose of this experiment was to examine the effects of social environment and social status on coronary artery and aortic atherosclerosis in adult male cynomolgus monkeys (Macaca fascicularis). Thirty experimental animals were assigned to six groups of five members each, and all animals were fed a moderately atherogenic diet (43% of calories as fat, 0.34 mg cholesterol/Cal) for 22 months. Group memberships were changed periodically among 15 monkeys (unstable social condition) and remained fixed throughout the experiment in the remaining animals (stable social condition). Within each condition, individual monkeys were classified as either dominant or subordinate animals, based on dyadic patterns of aggression and submission. At necropsy, the coronary arteries were subjected to pressure fixation and five sections each were taken from the left anterior descending, left circumflex, and right coronary arteries. The mean intimal area measurement, based on all arterial sections, served as a coronary index for each animal. Results indicated that dominant animals in the unstable condition had significantly greater coronary artery atherosclerosis than dominant monkeys housed in stable social groups. Coronary artery atherosclerosis in the unstable dominants was also greater than among similarly housed (i.e., unstable) subordinates. A similar pattern was observed in the abdominal aorta, but was not statistically significant. No significant differences or similar patterns were seen in the thoracic aorta. Additional analyses revealed that the coronary artery effects were not due to concomitant differences in total serum cholesterol or high density lipoprotein cholesterol concentrations, blood pressures, ponderosity, or fasting glucose concentrations among the experimental animals. Behaviorally, manipulation of group memberships intensified agonistic encounters and disrupted patterns of affiliative interaction between dominant and subordinate monkeys. Overall, these results suggest that social dominance (an individual behavioral characteristic) is associated with increased coronary artery atherosclerosis, but only under social conditions that provide recurrent threats to the status of dominant animals (i.e., under behavioral challenge).

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    • "We observed a significant increase in coronary plaque size and degree of stenosis after chronic intermittent mental stress, which presumably contributed to the increased occurrence of myocardial infarctions. Also Cynomolgus monkeys exposed to mental stress develop more severe coronary artery atherosclerosis [13] and job insecurity in humans is known to negatively affect coronary heart disease [5], confirming the validity of the ApoE À/À Fbn1 C1039Gþ/À mouse model. Furthermore, the coronary arteries of stressed ApoE À/À Fbn1 C1039Gþ/À mice showed a marked increase in perivascular fibrosis, in which the renin-angiotensin-aldosterone system is a known key player [25]. "
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    ABSTRACT: Vulnerable atherosclerotic plaques are prone to plaque rupture leading to acute cardiovascular syndromes and death. Elucidating the risk of plaque rupture is important to define better therapeutic or preventive strategies. In the present study, we investigated the effect of chronic intermittent mental stress on atherosclerotic plaque stability and cardiovascular mortality in apolipoprotein E-deficient (ApoE(-/-)) mice with a heterozygous mutation in the fibrillin-1 gene (Fbn1(C1039G+/)(-)). This mouse model displays exacerbated atherosclerosis with spontaneous plaque ruptures, myocardial infarction and sudden death, when fed a Western-type diet (WD). Female ApoE(-/-)Fbn1(C1039G+/-) mice were fed a WD for up to 25 weeks. After 10 weeks WD, mice were divided in a control (n = 27) and mental stress (n = 29) group. The chronic intermittent mental stress protocol consisted of 3 triggers: water avoidance, damp bedding and restraint stress, in a randomly assigned order lasting 6 h every weekday for 15 weeks. Chronic intermittent mental stress resulted in a significant increase in the amount of macrophages in atherosclerotic plaques of the proximal ascending aorta, whereas type I collagen and fibrous cap thickness were decreased. The coronary arteries of mental stress-treated mice showed larger plaques, more stenosis, and an increased degree of perivascular fibrosis. Moreover, myocardial infarctions occurred more frequently in the mental stress group. As compared to the control group, the survival of stressed ApoE(-/-)Fbn1(C1039G+/-) mice decreased from 67% to 52% at 25 weeks WD, presumably due to myocardial infarctions. In conclusion, chronic intermittent mental stress promotes plaque instability, myocardial infarctions, and mortality of ApoE(-/-)Fbn1(C1039G+/-) mice. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Atherosclerosis 07/2015; 242(1):288-294. DOI:10.1016/j.atherosclerosis.2015.07.025 · 3.99 Impact Factor
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    • "Monkeys were separated daily for several hours during operant behavioral sessions and feeding. Social status had previously been determined for each monkey according to the outcomes of agonistic encounters using procedures similar to those described previously (see Kaplan et al., 1982; Czoty et al., 2005, 2009). Briefly, two observers separately conducted several 15-minute observation sessions per pen. "
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    ABSTRACT: Dopamine D2/D3 receptor partial agonists have been suggested as medications for cocaine dependence. These experiments examined the effect of acute and repeated administration of drugs with varying intrinsic efficacy at D2/D3 receptors on the relative reinforcing strength of cocaine. Use of socially housed cynomolgus monkeys permitted the assessment of the whether social status, known to influence D2/D3 receptor availability, influenced the behavioral effects of D2/D3 receptor compounds. The high-efficacy agonist R(-)-norpropylapomorphine ((-)-NPA), low-efficacy agonist aripiprazole (ARI) and antagonist eticlopride (ETIC) were administered acutely to monkeys self-administering cocaine under a food-cocaine choice procedure in which a cocaine self-administration dose-effect curve was determined daily. The effects of 5-day treatment with ARI and (-)-NPA were characterized under conditions in which monkeys did (ARI) or did not (ARI and (-)-NPA) self-administer cocaine during treatment. When administered acutely, ARI and ETIC increased choice of low cocaine doses and only (-)-NPA decreased choice of higher cocaine doses and cocaine intake; effects were similar across social ranks. When administered repeatedly while self-administration occurred only on days 1 and 5 of treatment, ARI, but not (-)-NPA, decreased cocaine choice in dominant monkeys, whereas (-)-NPA but not ARI did so in subordinates. When dominant monkeys self-administered cocaine all five days of ARI treatment, however, these effects were not observed. The results indicate that the behavioral effects of D2/D3 receptor agonists can differ according to intrinsic efficacy and subject characteristics. Moreover, these results suggest that exposure to cocaine during treatment can counteract treatment-induced reductions in the reinforcing effects of cocaine.
    Journal of Pharmacology and Experimental Therapeutics 12/2012; 344(2). DOI:10.1124/jpet.112.201012 · 3.97 Impact Factor
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    • "In landmark studies, Kaplan and coworkers showed that atherosclerosis development was accelerated in dominant male cynomolgus monkeys living in unstable hierarchies [5] [6]. The effect on atherosclerosis was inhibited by nonselective í µí»½-blockade using propranolol [7]. "
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    ABSTRACT: A few studies in animals and humans suggest that metoprolol (β1-selective adrenoceptor antagonist) may have a direct antiatherosclerotic effect. However, the mechanism behind this protective effect has not been established. The aim of the present study was to evaluate the effect of metoprolol on development of atherosclerosis in ApoE(-/-) mice and investigate its effect on the release of proinflammatory cytokines. Male ApoE(-/-) mice were treated with metoprolol (2.5 mg/kg/h) or saline for 11 weeks via osmotic minipumps. Atherosclerosis was assessed in thoracic aorta and aortic root. Total cholesterol levels and Th1/Th2 cytokines were analyzed in serum and macrophage content in lesions by immunohistochemistry. Metoprolol significantly reduced atherosclerotic plaque area in thoracic aorta (P < 0.05 versus Control). Further, metoprolol reduced serum TNFα and the chemokine CXCL1 (P < 0.01 versus Control for both) as well as decreasing the macrophage content in the plaques (P < 0.01 versus Control). Total cholesterol levels were not affected. In this study we found that a moderate dose of metoprolol significantly reduced atherosclerotic plaque area in thoracic aorta of ApoE(-/-) mice. Metoprolol also decreased serum levels of proinflammatory cytokines TNFα and CXCL1 and macrophage content in the plaques, showing that metoprolol has an anti-inflammatory effect.
    06/2011; 12(1):71-71. DOI:10.1016/S1567-5688(11)70329-4
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