Modeling the Exposome in Murine Cardiovascular Disease

Figures

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  Central Illustration. Modeling the Exposome in Murine Cardiovascular Disease

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  Figure 1. Bidirectional Mechanistic Interactions Between Sleep and Cardiovascular Disease in Mice (A) In mice, sleep fragmentation leads to reduced hypocretin generation by the lateral hypothalamus, which unleashes hematopoietic growth factor generation by bone marrow neutrophils to augment hematopoiesis and monocyte production, accelerating atherosclerosis. In the atherosclerotic lesions of mice with Jak2 clonal hematopoiesis, sleep fragmentation causes macrophage death, which signals through CELC4E on mutant macrophages to stimulate the NLRP3 and AIM2 inflammasomes and interleukin (IL)-1β generation to accelerate clonal hematopoiesis (CH)-driven atherosclerosis. (B) After myocardial infarction, monocytes are recruited to the brain where they generate tumor necrosis factor (TNF) in the thalamus to instigate sleep through the regulation of glutamatergic networks. HSC = hematopoietic stem cell.

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  Figure 2. Mechanisms Associating Stress and Cardiovascular Disease From Murine Experiments The murine models of restraint stress, chronic variable stress, and social defeat stress have uncovered novel mechanistic connections between stress and cardiovascular disease. These stress models regulate the activity of interconnected stress circuits among the periventricular hypothalamus (PVH), amygdala, locus coeruleus (LC), rostral ventrolateral medulla (RVLM), and the dorsal motor nucleus of the vagus (DMV). These circuits modulate peripheral stress responses through neuroendocrine, hypothalamic-pituitary-adrenal (HPA) axis, sympathetic nervous system (SNS), and vagus and motor nerves, which together affect cardiovascular physiology, inflammation, and ultimately cardiovascular disease.

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  Figure 3. Mechanisms by Which Voluntary Exercise Diminishes Murine Atherosclerosis In mice, voluntary exercise represses leptin production from visceral white adipose tissue, which signals through leptin receptor–positive (LepR+) bone marrow stromal cells to regulate HSC quiescence factors that restrain HSC turnover, monocytosis, and atherosclerosis. Voluntary exercise also activates the LC in the brain to promote plasma norepinephrine, which signals through the adrenergic receptor (ADR) β2 on lesional macrophages with CH mutations in Tet2 or Jak2 to repress inflammasome activation and atherosclerosis. Other abbreviations as in Figures 1 and 2.