Coronary Artery Atherosclerosis of Female Cynomolgus Monkeys
Although the importance of psychosocial influences on coronary artery atherosclerosis of both male and female human beings has been recognized for many years, the topic has not, until recently, become the subject of experimental studies. Over the past decade we have explored the usefulness of cynomolgus macaques for research on psychosocial influences on atherogenesis. In the design of our experiments, we have taken advantage of the well-established dominance structure found within social groups of these animals, recognizing that the characteristics of cynomolgus macaques that make them dominant in social groups (aggressiveness, competitiveness) are some of the same characteristics associated with the type A behavior profile of human subjects. We have also taken advantage of the chronic physiological changes that occur among socially subordinate female cynomolgus monkeys to understand better the effects of stress on “female protection.” Finally, we have utilized the observation that cynomolgus monkeys, like human beings, vary in their characteristic cardiovascular response to stress (some having markedly heightened sympathetic arousal to psychosocial stimulation) to evaluate the significance of this trait in coronary atherosclerosis.
Among female cynomolgus macaques, evidence has been obtained to show that subordinate social status is associated with chronically impaired ovarian function, lowered plasma concentrations of HDL, and increased heart rate hyperresponsivity to psychosocial stress, which together result in loss of “female protection” against coronary artery atherosclerosis.
The influence of contraceptive-steroid-induced decreases in plasma HDL cholesterol concentrations (HDL-C) on coronary artery atherosclerosis of female cynomolgus macaques has also been studied. The animals consumed a moderately atherogenic diet for about 3 years. Control monkeys received no medication. For the final 2 years, one group was treated with an intravaginal ring (IVR) containing 17-ß estradiol and levonorgestrel; one group received oral ethinyl estradiol and levonorgestrel (Ovral®) daily. Both treatments resulted in significant reductions in HDL-C (P < 0.01). About half of the females in each group had coronary artery plaques. Despite the lowering of HDL-C in both groups, IVR females had larger plaques (P < 0.04) and Ovral® females a tendency to smaller plaques than controls. At HDL-C above 30 mg/dl, Ovral® treatment was protective (P < 0.05). Pharmacological lowering of HDL-C in one situation exacerbated, and in another diminished, coronary atherosclerosis. The contrasting effect may relate to the kind or route of administration of estrogen.
KeywordsCynomolgus Monkey Atherogenic Diet Cynomolgus Macaque Contraceptive Steroid Female Monkey
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