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Ablation of Toll-like receptor 4 mitigates central blood pressure response during hyperhomocysteinemia
Nevena Jeremic1, Gregory J Weber, Anastasia Familtseva
1Department of Physiology, University of Louisville, Louisville, Kentucky, USA.
Objective:
The objective of this study was to define the mechanisms of homocysteine-induced effects on the aortic wall that promote vascular remodeling and hypertension as well as explore the role of Toll-like receptor 4 in homocysteine-induced effects.
Method:
Five strains of mice were utilized in this study: C57BL/6J, C3H/HeOuJ, CBS+/-, C3H/HeJ and CBS+/-/C3H. Aorta, heart and blood were collected at the end of the experiments. Blood pressure (BP) was recorded using noninvasive tail cuff method. To determinate effects of vasoactive agent and endothelial-dependent vasodilator on aorta contractility, we performed vascular function measurements. In addition, the expression of mitochondrial fusion and fission proteins, antioxidant markers and collagen fragments were assessed.
Results:
BP measurements demonstrated a significant increase in SBP and DBPs in CBS+/- mice compared with other groups. CBS+/- mice aorta had lower response to phenylephrine and acetylcholine compared with other groups; however, CBS+/-/C3H mice response was improved. Dynamin-related protein 1 protein expression was significantly upregulated in CBS+/- mice, whereas C3H mice showed downregulation. In addition, CBS+/- mice showed increased oxidative stress, inflammation and decreased nitric oxide. These effects were normalized in CBS+/-/C3H mice.
Conclusion:
Our findings demonstrate the dominance of endothelial cell mitochondrial fission over mitochondrial fusion in hyperhomocysteinemia and oxidative stress. This may explain the endothelial cell loss and dysfunction that follows collagen deposition, which contributes to inward aorta remodeling in hypertension.
Insights
High homocysteine levels promote hypertension and vascular remodeling by increasing mitochondrial fission in endothelial cells, leading to oxidative stress and inflammation. These effects were reversed in a specific mouse model, suggesting potential therapeutic targets.
Area of Science:
- Cardiovascular Research
- Vascular Biology
- Hypertension Mechanisms
Background:
- Hyperhomocysteinemia is linked to vascular remodeling and hypertension.
- The role of mitochondrial dynamics and Toll-like receptor 4 in these processes requires further elucidation.
Purpose of the Study:
- To investigate homocysteine's mechanisms on aortic wall, promoting vascular remodeling and hypertension.
- To explore the involvement of Toll-like receptor 4 in homocysteine-induced vascular effects.
Main Methods:
- Utilized five mouse strains, including CBS+/- mice, to study effects on aorta, heart, and blood.
- Assessed blood pressure, vascular function, and expression of mitochondrial proteins, antioxidant markers, and collagen.
Main Results:
- CBS+/- mice exhibited elevated blood pressure, reduced aortic response to vasoactive agents, increased oxidative stress, inflammation, and decreased nitric oxide.
- Mitochondrial fission protein (Dynamin-related protein 1) was upregulated in CBS+/- mice.
- Co-administration with C3H/HeJ strain normalized these detrimental effects.
Conclusions:
- Endothelial cell mitochondrial fission dominates over fusion in hyperhomocysteinemia, causing cell loss and dysfunction.
- This dysfunction, coupled with collagen deposition, contributes to inward aortic remodeling and hypertension.
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