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Hyperhomocysteinemia and its role in the development of atherosclerosis
A B Lawrence de Koning1, Geoff H Werstuck, Ji Zhou
1Department of Pathology and Molecular Medicine, McMaster University and the Henderson Research Centre, Hamilton, Ontario, Canada.
Insights
High homocysteine levels (HHcy) are a major risk factor for cardiovascular disease. Animal models confirm HHcy causes endothelial dysfunction and atherosclerosis, aiding research into treatments.
Area of Science:
- Cardiovascular Science
- Metabolic Disease Research
- Vascular Biology
Background:
- Hyperhomocysteinemia (HHcy) is a recognized risk factor for cardiovascular disease.
- HHcy arises from impaired homocysteine metabolism due to enzyme or vitamin cofactor deficiencies.
- Proposed mechanisms linking HHcy to cardiovascular disease include oxidative stress, ER stress, and inflammation.
Purpose of the Study:
- To investigate the causal relationship between HHcy and cardiovascular pathology.
- To utilize animal models for understanding HHcy's cellular mechanisms in cardiovascular disease.
- To identify potential therapeutic targets for HHcy-related cardiovascular conditions.
Main Methods:
- Employing genetic and diet-induced animal models to establish HHcy.
- Assessing endothelial dysfunction in HHcy models.
- Evaluating the progression of atherosclerosis in HHcy models.
Main Results:
- Demonstrated a direct causal link between HHcy and endothelial dysfunction.
- Confirmed HHcy's role in accelerating atherosclerosis development.
- Validated animal models as effective tools for studying HHcy's cardiovascular impact.
Conclusions:
- HHcy is a direct cause of endothelial dysfunction and atherosclerosis.
- Animal models are crucial for elucidating HHcy's pathogenic mechanisms.
- These models offer a platform for developing novel cardiovascular disease therapies.
Abstract:
Numerous epidemiological studies have demonstrated that hyperhomocysteinemia (HHcy) is a strong and independent risk factor for cardiovascular disease. HHcy can result from a deficiency in the enzymes or vitamin cofactors required for homocysteine metabolism. Several hypotheses have been proposed to explain the cellular mechanisms by which HHcy promotes cardiovascular disease, including oxidative stress, endoplasmic reticulum (ER) stress and the activation of pro-inflammatory factors. Studies using genetic- and diet-induced animal models of HHcy have now demonstrated a direct causal relationship between HHcy, endothelial dysfunction and accelerated atherosclerosis. These recently established animal models of HHcy provide investigators with important in vivo tools to (i) further understand the cellular mechanisms by which HHcy contributes to endothelial dysfunction and atherosclerosis, and (ii) develop therapeutic agents useful in the treatment of cardiovascular disease.