Philip McCabe, Ph.D.

Professor
Chairman, Department of Psychology
University of Illinois, 1982

Central Nervous System mechanisms in emotional behavior; Behavioral factors in heart disease.

Publications

Szeto, A., Rossetti, M.A., Mendez, A.J., Noller, C.M., Herderick, E.E., Gonzales, J.A., Schneiderman, N., and McCabe, P.M. (2012) Oxytocin administration attenuates atherosclerosis and inflammation in Watanabe Heritable Hyperlipidemic rabbits. Psychoneuroendocrinology, DOI:10.1016/j.psyneuen.2012.08.009.

Noller, C.M., Szeto, A., Mendez, A.J., Llabre, M.M., Gonzales, J.A., Rossetti, M.A., Schneiderman, N., and McCabe, P.M. (2012) The influence of social environment on endocrine, cardiovascular and tissue responses in the rabbit. International Journal of Psychophysiology, DOI: 10.1016/j.ijpsycho.2012.04.008.

Szeto, A., McCabe, P.M., Nation, D.A., Tabak, B.A., Rossetti, M.A., McCullough, M.E., Schneiderman, N., and Mendez, A.J. (2011) Evaluation of enzyme immunoassay and radioimmunoassay methods for the measurement of plasma oxytocin. Psychosomatic Medicine, 73 (5): 393-400.

Tabak, B.A., Szeto, A., Mendez, A.J., McCabe, P.M., and McCullough, M.E. (2011) Oxytocin indexes relational distress following interpersonal harms in women. Psychoneuroendocrinology, 36(1):115-22. Epub 2010 Aug 4.

Nation, D.A. , Szeto, A., Mendez, A.J., Brooks, L.G., Zaias, J., Gonzales, J., Noller, C., Schneiderman, N., and McCabe, P.M. (2010) Oxytocin attenuates atherosclerosis and adipose tissue inflammation in ApoE -/- mice. Psychosomatic Medicine. 72(4): 376-82. Epub 2010 Apr 5.

Nation, D.A., Schneiderman, N., and McCabe, P.M. (In Press) Biopsychosocial Factors in Coronary Artery Disease. In S. Waldstein, W. Kop, and L. Katzel (Eds.), Handbook of Cardiovascular Behavioral Medicine. Springer: New York.

Tabak, B.A., Szeto, A., Mendez, A.J., McCabe, P.M., and McCullough, M.E. (2011) Oxytocin indexes relational distress following interpersonal harms in women. Psychoneuroendocrinology, 36(1):115-22. Epub 2010 Aug 4.

Mendez, A.J., Goldberg, R.B., & McCabe, P.M. (2010) The metabolic syndrome, obesity, and insulin resistance. In A. Steptoe and K. Freedland (Eds.) The Handbook of Behavioral Medicine, Springer: New York, pp. 705-721.

Nation, D.A., Schneiderman, N., and McCabe, P.M. (2010) Animal models in Health Psychology Research. In J. Suls, K. Davidson, and R. Kaplan (Eds.), Handbook of Health Psychology and Behavioral Medicine, Guilford Press: New York, pp. 163-181.

Szeto, A., Nation, D.A., Mendez, A.J., Dominguez-Bendala, J., Brooks, L.G., Schneiderman, N., and McCabe, P.M. (2008) Oxytocin attenuates NADPH-dependent superoxide activity and IL-6 secretion in macrophages and vascular cells. American Journal of Physiology: Endocrinology and Metabolism. Dec;295(6):E1495-501. Epub 2008 Oct 21.

Nation, D.A., Gonzales, J.A., Mendez, A.J., Zaias, J., Szeto, A., Brooks, L.G., Paredes, J., D'Angola, A., Schneiderman, N., and McCabe, P.M. (2008) The effect of social environment on markers of vascular oxidative stress and inflammation in the Watanabe Heritable Hyperlipidemic Rabbit. Psychosomatic Medicine, 70(3):269-75. Epub 2008 Feb 6.

Paredes, J., Szeto, A., Levine, J.E., Zaias, J., Gonzales, J., Mendez, A.J., Llabre, M.M., Schneiderman, N., and McCabe, P.M. (2006) Social environment influences hypothalamic oxytocin in the WHHL rabbit. Psychoneuroendocrinology, 31, 1062-1075.

Gonzales, J.A., Szeto, A., Mendez, A.J., Goldberg, R.B., Caperton, C.V., Paredes, J., Zaias, J., Schneiderman, N., and McCabe, P.M. (2005) Effect of behavioral interventions on insulin sensitivity and atherosclerosis in the Watanabe Heritable Hyperlipidemic Rabbit. Psychosomatic Medicine, 67, 172-178.

Szeto, A., Gonzales, J.A., Sptizer, S.B., Levine, J.E., Schneiderman, N., and McCabe, P.M. (2004) Glucocorticoid responses of Watanabe Heritable Hyperlipidemic rabbits and New Zealand White rabbits. Psychoneuroendocrinology, 29, 861-866.

McCabe, P.M., Gonzales, J.A., Zaias, J., Szeto, A., Kumar, M., Herron, A.J., & Schneiderman, N. (2002) Social environment influences the progression of atherosclerosis in the Watanabe Heritable Hyperlipidemic Rabbit. Circulation, 105, 354-359.

Research

My research, which has been supported continuously for 25 years by an NHLBI Program Project, deals with the influence of social-emotional behavior on the development of cardiovascular disease. More specifically, I have studied the role of social environment on the progression of atherosclerosis in the Watanabe Heritable Hyperlipidemic Rabbit (WHHL), an animal that spontaneously develops atherosclerosis due to a genetic defect in cholesterol clearance. My lab is examining CNS regulation of neuroendocrines during complex social behavior, and the role of these hormones and autonomic function in vascular pathology. Of particular interest is the potential role of oxytocin, which may be released into the blood preferentially during stable social conditions, in suppressing vascular oxidative stress and inflammation. Currently, we are investigating this possibility in cell cultures, as well as during in vivo experiments. In this work I am collaborating with Neil Schneiderman and Maria Llabre from the Psychology Department, Ron Goldberg and Armando Mendez from the Diabetes Research Institute and the Department of Medicine, and Julie Zaias from the Division of Comparative Pathology and the Division of Veterinary Resources. A description of specific studies are listed below:

Social environment and the progression of atherosclerosis in the WHHL

Several years ago, we published the first demonstration that social environment can influence the progression of atherosclerosis in the WHHL model (McCabe et al., 2002). WHHL rabbits were assigned to one of three social/behavioral groups: an Unstable group, in which unfamiliar rabbits were paired daily, with the pairing switched each week, a Stable group, in which littermates were paired daily for the entire study, and an Individually-Caged group. The Stable group exhibited more affiliative social behavior and less agonistic behavior than the Unstable group, and significantly less aortic atherosclerosis than each of the other two groups. Although the Unstable and Individually-Caged groups had comparable aortic lesion areas, the severity of the disease progressed faster in the Unstable group, as indexed by a larger area of calcification and increased fibrous cap thickness in complex lesions (see Figure 1). Lesions in the Individually-Caged group consisted primarily of foams cells (i.e., grade 3). The Unstable group showed increased agonistic behavior and signs of chronic adrenocortical and gonadal activation, whereas the Individually-Caged group was relatively sedentary, had low glucocorticoid levels, and was hyperinsulinemic compared to the other groups. The study demonstrated that social environment can slow, as well as accelerate, the progression of atherosclerosis. It also emphasized the importance of behavioral factors in atherogenesis, even in a model of disease with strong genetic determinants.

Figure 1

Figure 1. Examples of atherosclerotic lesions in WHHL rabbits. Left photo, grade 3 lesion consisting primarily of foam cell infiltration into the vessel wall. Right photo, more complex grade 5a lesion containing foam cells, necrosis, and formation of a fibrous cap.

In Vitro Studies: Monocytes and macrophages express oxytocin receptors and oxytocin decreases NADPH oxidase activity in human vascular cells and IL-6 secretion in macrophages.

Previously, we demonstrated that plasma oxytocin (OT) is elevated in WHHL rabbits exposed to a stable social environment relative to WHHLs in the other two social conditions. It was hypothesized that this nonapeptide may play a role in slowing the progression of atherosclerosis in these animals by directly influencing pathophysiological processes in the vessel wall. Therefore, we just completed a study to examine the effect of oxytocin on atherogenic processes in vitro (Szeto et al., 2008). More specifically, we are using cultured human vascular cells to examine NAD(P)H oxidase activity (a marker of vascular oxidative stress), cell adhesion molecule (CAM) expression and IL-6 secretion (markers of vascular inflammation) following incubation with OT. Initially, we examined the expression of the oxytocin receptor in human endothelial, smooth muscle, and monocyte/macrophage cells (Figure 2). These data confirm that endothelial and smooth muscle cells express a specific immunoreactive band (Figure 2A) with the expected molecular weight of the OT-receptor (~65 kDa). Additionally, we showed for the first time that the human THP-1 monocytic cell line also express an immunoreactive band consistent with the expression of the OT-receptor. Additional studies (Figure 2B) show that the receptor is expressed in the mouse macrophage cell line RAW 267, THP-1 cells differentiated into macrophages by treatment with phorbol myristate acetate (1nM for 72 hours) and importantly, freshly isolated human peripheral blood monocytic cells (PBMC). These results indicate that monocytes/macrophages express the OT-receptor; the functional role of this protein remains to be elucidated. We next examined the effect of chronic OT exposure (18 hours at the indicated dose) on OT-receptor expression in human aortic endothelial cells (Figure 2C). After 18 hours in the presence of 10 or 100 pM OT, there was no observable difference in receptor immunoreactivity compared to control cells.

Figure 2

Figure 2: Oxytocin receptor (OTR) expression in endothelial, smooth muscle and monocytic cells. Cultured cells were solubilized in SDS-sample buffer and 8 µg cell protein were separated by PAGE followed by immunoblotting with a specific anti-OTR polyclonal antibody (AlphaDiagnostics). In panel B, THP-1 monocytes were differentiated into macrophage like cells by treatment with phorbol esters (1 nM) for 72 hours and human peripheral mono-nuclear cells (PBMCwere freshly prepared by the Ficoll gradient method. Panel C. near confluent cultures of human aortic endothelial cells were maintained for 18 hours with the indicated level of OT, then analyzed for expression of OTR. Bar graph represents the integrated density value of immunoreacted OTR normalized to actin.

Figure 3

Figure 3. Effect of oxytocin (OT) treatment on NAD(P)H oxidase activity in (A) cultured human aortic endothelial cells and the (B) THP-1 human monocytic cell line. Cells were treated with the indicated concentration of OT for 1 hour then assayed for NADPH oxidase generated superoxide was detected by the lucigenin (5 µM) enhanced chemiluminescence method. Results are the mean ± SD of 4 replicates (endothelial cells) or mean ± range of duplicates (THP-1 cells) and representative of at least two individual experiments. For Panel A (endothelial cells), repeated measures ANOVA revealed a significant condition (control vs.10 pM oxytocin) by time interaction, F (7,42) = 8.02, p <.0001, and a significant effect for condition, F (1,6)) =10.72, p < .02. For Panel B (monocytes), there was a significant condition by time interaction, F (21,28) = 16.47, p<.0001, and a significant condition effect, F (3,4) = 6.77, p < .05, indicating that all concentrations of OT significantly reduced NADPH oxidase activity.

Figure 4

Figure 4. Effect of oxytocin (OT) on tumor necrosis factor-(TNF) mediated induction of intracellular adhesion molecule (ICAM) expression. Human aortic endothelial cells were cultured to near confluence, incubated without (Control) or with 10 pM OT, then exposed to 1 ng/ml TNF. After 4 hours, the cells were harvested and 8 µg of solubilized protein were subjected to immunoblotting for ICAM and actin (to control for sample loading). Bars represent the relative integrated density value (Rel IDV) for the immunoreactive bands (inset) normalized for actin (mean ± range of duplicate samples).

The effect of OT treatment on TNF-mediated increases in the cell adhesion molecule ICAM was examined in cultured endothelial cells. Exposure of endothelial cells to 1 ng/ml TNF induced over a 100-fold increase in expression of ICAM from nearly undetectable levels in control cells (not shown). In early studies, pretreatment with 1000 pM OT [a concentration chosen based on the Kd of the ligand for its receptor (~1 to 2 nM)] prior to addition of TNF caused an approximately 20% decrease in ICAM expression compared to cells treated only with TNF. Similar studies were conducted utilizing concentrations of OT expected in the circulation (10 pM) and resulted in a 21% reduction in ICAM expression (Figure 4). Although these are relatively modest reductions in expression, considering the potency of TNF induction of ICAM, it is possible that under conditions where more modest increases of ICAM occur, OT may have a greater effect on relative protein induction.

Lastly, we have recently demonstrated that physiological concentrations of OT (i.e., 10 pM) attenuate LPS-stimulated IL-6 release from THP-1 macrophages by approximately 50% (see Figure 5). IL-6 is an important proinflammatory cytokine, and is likely to play a major role in the pathophysiology of atherosclerosis. This attenuation was reversed by administration of the OT receptor antagonist, atosaban, which demonstrates that OT's effects are mediated through the OT receptor.

Figure 5

Figure 5. LPS-stimuated IL-6 secretion from THP-1 macrophages. Note the dose dependent attenuation of IL-6 secretion by OT, and the reversal of this effect by adminstration of atosaban (AT).

Taken together, these novel findings suggest OT attenuates vascular oxidative stress and inflammation in vascular cells and macrophages, which are two important pathophysiological processes in atherosclerosis. The fact that OT receptors are found in monocytes and macrophages, and that OT decreases both superoxide production and release of an important proinflammatory cytokine from these cells, suggests a potentially larger role for OT in the attenuation of disease processes throughout the body.

Oxytocin Attenuates Atherosclerosis and Adipose Tissue Inflammation in Socially Isolated ApoE-/- Mice

Several studies, including work from our lab, have found that hyperlipidemic animals housed in isolated or stressful social environments display more extensive atherosclerosis than those housed in an affiliative social environment. The neurohypophyseal peptide, oxytocin (OT), may be involved in both affiliative social behavior and cardiovascular homeostasis, suggesting a role in mediating the benefits of positive social interactions on atherosclerosis. In a recent study (Nation et al., in press) we sought to determine the effect of exogenous OT administration on inflammation and atherosclerosis in socially isolate). Forty-three, 12-week-old, apoE-/- mice were surgically implanted with osmotic mini-pumps containing oxytocin (n=23) or vehicle (n=20). Blood was taken at baseline and after 6 and 12 weeks of treatment. After 12 weeks of treatment animals were sacrificed and samples of adipose tissue were dissected from a subset of OT (n=12) and vehicle (n=12) treated animals and incubated in culture media for 6 hours. Media samples were analyzed for IL-6 concentration corrected by sample dry-weight. Aortas were dissected, formalin-fixed, and stained with oil-red O for en face quantification of lesion area. T-tests were used to compare group means on measures of percent lesion area and IL-6 concentrations. There were no group differences in plasma lipids over the 12-week treatment. Adipose tissue samples taken from OT treated animals secreted significantly less IL-6 over 6 hrs (P<0.01; see figure 6). OT treated animals displayed significantly less atherosclerosis in the thoracic aorta (P<0.05; see Figure 7). These results indicate that peripheral OT administration can inhibit atherosclerotic lesion development and adipose tissue inflammation, suggesting a potential role for this neuropeptide in mediating the benefits of stable group housing on atherosclerosis.

Figure 6

Figure 6. Analysis of IL-6 secretion from visceral adipose tissue samples over 6 hours of ex vivo incubation revealed that samples taken from OT treated animals produced less IL-6 than those of the vehicle control group. Values are expressed as picograms IL-6 per gram of sample dry-weight. Data represent means and standard errors.

Figure 7

Figure 7. Extent of atherosclerosis in control and oxytocin treated apoE-/- mice. (A) Lesion prevalence maps display the cumulative aortic area covered by atherosclerotic lesions, as indicated by oil-red-O staining, with darker areas representing greater lesion frequency in a given location. Visual inspection of prevalence maps revealed that nearly all of the disease occurred in the aortic arch and the thoracic aorta (circled regions), with an apparent difference in lesion prevalence between groups within the thoracic region (arrows). Quantitative analysis of aortic percent lesion area within the thoracic aorta (B) and the aortic arch (C), confirmed the significant group difference in the thoracic aorta. Data represent means and standard errors.

In Vitro Studies: The influence of oxytocin on proinflammatory cytokine release from cultured fat cells.

We have begun to study the potential role of OT in attenuating systemic inflammatory response by inhibiting the secretion of proinflammatory cytokines from adipose tissue. It has been well established that increased adiposity is a risk factor for a variety of diseases, including atherosclerosis and heart disease. It was hypothesized that cytokine secretion by adipose tissue, and particularly by adipocytes, could be attenuated by OT, providing another potential mechanism by which OT may slow the progression of atherosclerosis. In both cultured rat adipose tissue and isolated rat adipocytes, we demonstrated the presence of OT receptors . Subsequently, isolated adipocytes were incubated with physiological concentrations of OT. It was found that OT attenuated basal release of IL-6 from the cells, and also attenuated LPS-stimulated release of IL-6 . These data suggest that OT may have broad anti-inflammatory effects on tissues outside the cardiovascular system, and may play an important role in the attenuation of a variety of disease processes

The influence of OT on the progression of atherosclerosis in the Watanbe Heritable Hyperlipidemic Rabbit (WHHL).

Previous work in our lab using the WHHL model demonstrated that a stable social environment, characterized by increased affiliative behavior and relatively less agonistic behavior, slowed the progression of atherosclerosis by about 50% compared to an unstable social environment or social isolation (McCabe et al., 2002). As mentioned above, OT may be involved in both affiliative social behavior and cardiovascular homeostasis, suggesting a role in mediating the benefits of positive social interactions on atherosclerosis. Therefore, we are currently conducting a study to examine the influence of chronic OT infusion on the progression of atherosclerosis, inflammation and oxidative stress in WHHL rabbits.

Twenty-eight WHHLs were assigned to either an OT infusion group or vehicle infusion group (via osmotic minipumps), and were studied over a 4-month period. We sampled blood for measurement of plasma OT, lipids, cytokines (IL-6, TNF-alpha, MCP-1, IL-1-beta, IL-10), and glucocorticoids, and we collected 24 hour urine samples for measurement of urinary catecholamines. At the end of the study, when the animals were 7 months of age, the rabbits were sacrificed and the aorta, heart and adipose tissue were collected for histological and biochemical analyses. Similar to the ApoE (-/-) model, we hypothesize that OT will slow the progression of atherosclerosis in a site specific manner. It is also hypothesized that inflammatory neuroendocrine markers will be related to the group differences in disease. Preliminary analyses suggest that OT infusion significantly reduces atherosclerosis in the thoracic and abdominal aorta relative to the control group. In addition, it appears that OT reduces proinflammatory cytokine expression in visceral fat stores by up to 50%. These data are consistent with the findings from the previously described ApoE (-/-) OT infusion study.

Insulin metabolic variables and behavioral interventions in the WHHL

In our first WHHL study, the fact that individually-caged WHHLs exhibited increased body weight, behavioral inactivity, hyperinsulinemia, and elevated heart rate suggested that insulin metabolic variables play a role in the progression of atherosclerosis in WHHL rabbits. A recently published study from our lab (Gonzales et al., 2005) sought to determine: a) if young, individually-caged WHHLs are insulin resistant relative to NZW rabbits and b) whether dietary or exercise interventions can improve insulin sensitivity and slow the development of atherosclerosis in these animals. Forty-two WHHLs were assigned to either a dietary, exercise, or control condition, and 12 NZWs were used as a comparison control group. The intervention ran from 3 to 7 months of age, and all animals received an intravenous glucose tolerance test at the beginning and end of the intervention. It was found that WHHLs were insulin resistant relative to NZWs at 3 months of age. Whereas the dietary intervention was effective in controlling insulin resistance, WHHLs in the exercise group without dietary restriction and the control group exhibited significant increases in insulin resistance. Despite the significant changes in insulin sensitivity, none of the interventions significantly influenced the progression of atherosclerosis. It was concluded that young WHHLs are insulin resistant during an early period when atherosclerosis is developing rapidly. Dietary restriction, but not exercise without weight control, is effective in controlling insulin metabolic variables in the WHHL model. Although dietary intervention can reduce cardiovascular risk factors such as insulin resistance, it is not effective in slowing the development of atherosclerosis in these genetically dyslipidemic animals. This may have been due, in part, to the fact that dietary restriction significantly increased plasma cholesterol relative to the other groups. Exercise training, without dietary control, also did not influence the progression of disease in WHHLs.

Teaching

Sample Syllabi
PSY 402 Psychobiology