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Published on: April 30, 2020
Fenofibrate Modulates HO-1 and Ameliorates Endothelial Expression of Cell Adhesion Molecules in Systolic Heart
Wei-Hsian Yin1, Jaw-Wen Chen2, Yung-Hsiang Chen3
1Heart Center, Cheng-Hsin General Hospital; ; Faculty of Medicine, National Yang-Ming University;
Insights
Fenofibrate may benefit heart failure (HF) patients by reducing endothelial activation. This drug helps regulate heme oxygenase-1 (HO-1) expression, mitigating the harmful effects of cell adhesion molecules in HF.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Pharmacology
Background:
- Endothelial activation and dysfunction are key in heart failure (HF) pathogenesis.
- Cell adhesion molecules (CAMs) play a role in endothelial dysfunction.
- Heme oxygenase-1 (HO-1) is implicated in regulating endothelial function.
Purpose of the Study:
- To investigate fenofibrate's effect on endothelial CAM expression in HF.
- To determine if fenofibrate's effects are mediated by HO-1 regulation.
- To explore fenofibrate's potential as a therapeutic agent for systolic HF.
Main Methods:
- Cultured human pulmonary artery endothelial cells (HPAECs) were treated with serum from HF patients or healthy volunteers.
- Analysis of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and HO-1 expression via mRNA and Western blot.
- Investigated the impact of HO-1 manipulation (siRNA, inducer) and fenofibrate pretreatment.
Main Results:
- HF patient serum increased CAMs and decreased HO-1 expression in HPAECs.
- HO-1 suppression exacerbated CAM expression, while HO-1 induction suppressed it.
- Fenofibrate pretreatment prevented HF serum-induced endothelial activation and normalized HO-1 levels.
Conclusions:
- Fenofibrate ameliorates endothelial activation in HF by upregulating HO-1.
- This suggests a therapeutic role for fenofibrate in managing systolic heart failure.
- HO-1 regulation is a key mechanism for fenofibrate's vascular protective effects in HF.
Background:
Endothelial activation and dysfunction have been implicated in the pathogenesis and progression of heart failure (HF). In the present study, we investigated if endothelial expression of cell adhesion molecules (CAMs) is inhibited by fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist with anti-inflammatory and vascular protective effects, through the regulation of heme oxygenase-1 (HO-1).
Methods:
We recruited a total of 20 patients with advanced systolic HF and 20 healthy volunteers who all provided blood samples. Cultured human pulmonary artery endothelial cells (HPAECs) were treated with 70% sera obtained from study individuals, with or without pretreatment with fenofibrate. The endothelial expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and HO-1 were analyzed by mRNA expression and Western blot.
Results:
Stimulation of cultured HPAECs with serum from HF patients significantly activated nuclear factor-κ B (NF-κB) and increased VCAM-1 and ICAM-1 expression but attenuated HO-1 expression. Immunohistochemistry study also confirmed that CAMs were up-regulated, whereas HO-1 was down-regulated in HF patients. HO-1 small interfering RNA significantly suppressed HO-1 expression and exaggerated the HF serum-induced CAM expression, whereas HO-1 inducer cobalt protoporphyrin IX simultaneously stimulated HO-1 expression and suppressed CAM expression. Pretreatment with fenofibrate prevented the decrease of HO-1 expression and the activation of NF-κB as well as the increase of CAM expression that induced by HF patient serum.
Conclusions:
Our study demonstrated that fenofibrate may exert beneficial effects in patients with systolic HF through regulation of HO-1 expression and amelioration of endothelial activation.
Key Words:
Cell adhesion molecules; Endothelial cells; Heart failure; Heme oxygenase-1; Peroxisome proliferator-activated receptor-α.
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