Findings from the new mouse model may help understand how prolonged and severe depression and stress increase the risk of cardiovascular disease, according to preliminary research presented at the American Heart Association’s Vascular Discovery Sessions: From Genes to Medicine, Scientific Sessions 2022. The meeting is being held from May 12-14, 2022, in Seattle, the premier global exchange of the latest advances in new and emerging scientific research in atherosclerosis, thrombosis, vascular biology, peripheral vascular disease, vascular surgery, and functional genomics.
“Previous research has shown that major depressive disorders and anxiety caused by prolonged and intense stress have been associated with an increased incidence of cardiovascular disease. The risk of cardiovascular disease increases in proportion to the severity of depression,” said the study’s lead author, Özlem Tuvanli Kirichibasi. Dr.. , a postdoctoral fellow in the laboratory of Edward A. Fisher, MD, PhD, MSc in Public Health, FAHA, at the Cardiovascular Research Center at NYU Grossman School of Medicine in New York City. “When major depressive disorder and cardiovascular disease are present, the prognosis is worse for both conditions.”
The researchers say their study is the first to use a mouse model of chronic stress and depression to investigate whether and how chronic stress might affect cholesterol-lowering medications.
The researchers examined mice that lacked the low-density lipoprotein receptor (LDLr), which is needed to remove harmful cholesterol from the body. These mice, like people born lacking the receptors, are prone to a buildup of fats in the arteries called plaques, and are prone to early and serious cardiovascular disease. Unstable plaques can break (prone to rupture) causing blood clots to form that block blood flow, which can lead to a heart attack or stroke. To mimic the development of fatty deposits in humans, mice were fed a high-cholesterol diet for 24 weeks.
Half of the mice were exposed to social stress by sharing their living space with other, larger, more aggressive mice for short periods of time over ten days. After each stress episode, the mice were assessed for social avoidance and depressive or anxiety-like behaviors. The mice that exhibited the behaviors were classified as sensitive (depressed), and the other mice were classified as resilient (active coping). The other half of the mice (the control group) were not exposed to social stress.
Both susceptible (depressed) mice and control mice were treated with LDL-lowering drugs for 3 weeks, to mimic cholesterol treatment in humans. Previous studies found that when LDL-deficient mice were treated with lipid-lowering drugs, the arterial plaque became less inflammatory and more stable. After treatment, mice were tested for changes in the number of inflammatory cells in the plaques, the number of inflammatory white blood cells (monocytes) circulating in the blood, and the number of bone marrow cells, which are precursors to abundant immune cells in the plaque. Resilient mice were similarly evaluated, however, analyzes for this group of mice are still ongoing.
Analyzes found that, compared to rats not exposed to stress (the control group), rats exposed (depressed) from the group exposed to social stress:
- 50% rise in immune cells within arterial plaques;
- doubling the number of circulating monocytes, which are precursors of inflammatory cells;
- 80% increase in the number of immune cell precursors in the bone marrow.
- less collagen within the plaque in the arteries, which is an indicator of instability; And
- Similar reduction in lipid levels when compared to the response of control groups to LDL-lowering drugs.
“The main finding is that repetitive stress and the physiological and behavioral effects of antagonistic reactions (social defeat) appear to prevent the full beneficial changes to plaques that must be induced by lipid-lowering drugs,” Tuvanli Kirichibasi said.
The researchers also analyzed whether differences in the bone marrow of depressed mice might underlie the differences in plaque size and properties. To test this, another group of low-density lipoprotein-deficient mice received bone marrow transplants from either the susceptible (depressed) mice or the control group. After bone marrow transplantation, mice were fed a cholesterol-rich diet for 24 weeks.
Compared to mice that received bone marrow from the control group (without stress), mice that received bone marrow from the susceptible group had:
- 16% greater increase in immune cell precursors in the bone marrow;
- 50% greater increase in serum monocyte infections. And
- There is no change in plaque size, but rather in plaque composition, with a 23% increase in inflammation within plaques.
“By taking all of our findings together, we suggest that in situations where there is chronic stress, the harmful effects of high cholesterol can be improved and the benefits of low cholesterol reduced. This suggests that chronic stress mediates reprogramming at the genetic level, called epigenetic changes, in bone marrow precursors. for monocytes so that when the cells enter the plaques they are really more inflammatory,” Tovanlei Kirchibassi said.
This mouse model may provide a way to investigate and improve the treatment of prolonged depression and stress, and thus improve cardiovascular outcomes.
“These findings may indicate that more mental health attention is needed to combat cardiovascular disease, especially for people with depression or chronic stress. In the coming decades, new treatments for atherosclerosis should focus on altering immune responses, inhibiting inflammation, and enhancing These therapies have great potential to benefit people with cardiovascular disease, most likely especially in those with depression, Tuvanlei Kirichibasi said.
The researchers are currently collecting samples from mice that were exposed to the same repeated stress but seemed resilient to it. “We will conduct the same analyzes as this study to determine whether exposure to stress or susceptibility to stress induces changes in plaque that lead to plaque reduction or deterioration,” Tuvanli Kirichibasi said.
Co-authors are Bianca Scolaro, Ph.D.; Ada Weinstock, Ph.D.; Angelica Torres-Berio, Ph.D.; Eric Barris, Ph.D.; Florin Cathomas, MD; Kenny Chan, Ph.D.; Eric J. Nestler, MD, Ph.D.; Scott J. Russo, Ph.D.; and Edward A. Fisher, MD, PhD, MSc in Public Health, FAHA. The authors’ disclosures are listed in the abstract.
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