Summary: Mouse study reveals how depression and chronic stress can impact cholesterol-lowering drugs and influence heart disease risk.
Source: American Heart Association
Findings from a new mouse model may help understand how depression and prolonged, severe stress increase the risk of cardiovascular disease, according to preliminary research presented at the American Heart Association’s Vascular Discovery: From Genes to medicine scientific sessions 2022.
“Previous research has shown that major depressive disorder and anxiety due to prolonged and severe stress have been associated with an increased rate of cardiovascular disease. The risk of developing cardiovascular disease increases in proportion to the severity of depression,” said study lead author Özlem Tufanli Kireccibasi, Ph.D., a postdoctoral researcher in the lab of Edward A. Fisher, MD, Ph.D., MPH, FAHA, at the NYU Cardiovascular Research Center Grossman School of Medicine in New York.
“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 determine if and how chronic stress may affect cholesterol-lowering drugs.
The researchers examined mice that lacked a low-density lipoprotein (LDLr) receptor, which is needed to remove LDL (bad) cholesterol from the body. These mice, like people born without the receptor, are prone to developing fatty deposits called plaque in their arteries and are prone to premature and aggressive cardiovascular disease.
An unstable plaque (likely to rupture) can break apart, causing blood clots to form that block blood flow, which can lead to a heart attack or stroke. To mimic the development of fatty plaque in humans, the 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, aggressive mice for short periods of time over ten days. After each episode of stress, the mice were assessed for social avoidance and depression- or anxiety-like behaviors.
The mice that exhibited the behaviors were classified as responsive (depressed) and the rest were classified as resilient (effective coping). The other half of the mice (controls) were not exposed to social stress.
Sensitive (depressed) mice and control mice were treated with an LDL-lowering drug for 3 weeks, to mimic cholesterol processing in humans. Previous studies have shown that when LDLr-deficient mice are treated with lipid-lowering drugs, arterial plaque becomes less inflammatory and more stable.
After treatment, the mice were tested for changes in the number of inflammatory cells in their plaque, the number of inflammatory white blood cells (monocytes) circulating in the blood, and the number of bone marrow cells, precursors of abundant immune cells. . in wafer.
Resilient mice were assessed similarly, however, analyzes for this group of mice are ongoing.
The analyzes revealed that, compared to the non-stressed mice (the control group), the responsive (depressed) mice in the social stress-exposed group had:
- 50% higher increase in immune cells in the plaque of their arteries;
- double the number of circulating monocytes, precursors of inflammatory cells;
- 80% increase in the number of immune cell precursors in the bone marrow;
- less collagen in plaque in the arteries, which is an indicator of instability; and
- a similar decline in lipid levels compared to the response of control groups to anti-LDL drugs.
“The main finding is that repeated stress and the physiological and behavioral effects of hostile interactions (social defeat) appear to prevent the full beneficial plaque changes expected to be induced by lipid-lowering drugs,” said Tufanli Kireccibasi.
The researchers also analyzed whether differences in the bone marrow of depressed mice might underlie the differences in plaque size and characteristics.
To test this, another group of LDLr-deficient mice received a bone marrow transplant from either the susceptible (depressed) mice or the control group.
After the bone marrow transplant, the mice were fed a high-cholesterol diet for 24 weeks.
Compared to mice given bone marrow from the control (no stress) group, mice given bone marrow from the susceptible group had:
- 16% increase in immune cell precursors in bone marrow;
- 50% greater increase in inflammatory monocytes in the blood; and
- no change in plaque size, but in plaque composition, with 23% more inflammation in plaques.
“Taking all of our results together, we suggest that in chronic stressful situations, the adverse effects of high cholesterol may be increased and the benefits of low cholesterol may be diminished.
“This suggests that chronic stress induces reprogramming at the genetic level, called epigenetic changes, in the bone marrow precursors of monocytes, such that when the cells enter the plaques, they are already more inflammatory,” said Tufanli Kireccibasi. .
This mouse model may provide a means to study and improve the treatment of depression and prolonged stress and, in turn, improve cardiovascular outcomes.
“These results may indicate that greater attention to mental health is needed to combat cardiovascular disease, especially for people with depression or chronic stress. Over the next few decades, new therapies for atherosclerosis should focus on modifying immune responses, inhibiting inflammation and promoting plaque resolution pathways.
“These therapies have great potential to benefit people with cardiovascular disease, and probably especially those with depression,” said Tufanli Kireccibasi.
The researchers are now collecting samples from mice that were exposed to the same repeated stress but appeared to resist it.
“We will perform the same analyzes as this study to determine whether it is stress exposure or susceptibility to it that causes changes in plaque leading to less or worse plaque,” Tufanli said. Kireccibasi.
Co-authors are Bianca Scolaro, Ph.D.; Ada Weinstock, Ph.D.; Angelica Torres Berrio, Ph.D.; Eric Parise, Ph.D.; Flurin Cathomas, MD; Kenny Chan, Ph.D.; Eric J. Nestler, MD, Ph.D.; Scott J. Russo, Ph.D.; and Edward A. Fisher, MD, Ph.D., MPH, FAHA. Author disclosures are listed in the abstract.
About this mental health and heart disease research news story
Author: Press office
Source: American Heart Association
Contact: Press Office – American Heart Association
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Original research: Findings will be presented at the 2022 Scientific Sessions of the American Heart Association’s Vascular Discovery: From Genes to Medicine