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Published on: June 3, 2016
High-Density Lipoproteins from Coronary Artery Disease and Aortic Valve Stenosis Patients Differentially Regulate
María Luna-Luna1, Araceli Páez2, Felipe Massó2
1Department of Molecular Biology, Instituto Nacional de Cardiología "Ignacio Chávez", Mexico City 14080, Mexico.
Insights
High-density lipoproteins (HDL) from patients with coronary artery disease (CAD) and aortic valvular stenosis (AVS) differentially regulate gene expression in cardiac adipocytes, suggesting a potential therapeutic target for cardiovascular diseases.
Area of Science:
- Cardiovascular Biology
- Lipid Metabolism
- Molecular Medicine
Background:
- Statistical associations exist between high-density lipoprotein (HDL) subclasses and pro-calcifying gene expression in epicardial adipose tissue of patients with coronary artery disease (CAD) and aortic valvular stenosis (AVS).
- These associations suggest a potential causal link between HDL and gene expression regulation in epicardial adipose tissue, but experimental evidence is lacking.
Purpose of the Study:
- To investigate the direct effect of HDL isolated from CAD or AVS patients on the expression of key genes in cardiac adipocytes.
- To explore the underlying mechanisms, including HDL's structural characteristics and lipid internalization, in modulating adipocyte gene expression.
Main Methods:
- Utilized a novel in vitro model of cardiac adipocytes differentiated from rabbit stromal cells.
- Assessed the impact of HDL from CAD and AVS patients on the expression of genes related to calcification (OPN, BMP2, BMP4) and adipocyte phenotype (LEP, UCP, PER).
- Analyzed structural differences in HDL subclasses and demonstrated cholesterol internalization from reconstituted HDL into adipocytes.
Main Results:
- HDL from CAD or AVS patients differentially modulated the expression of BMP4 and LEP genes.
- HDL from both patient groups upregulated OPN gene expression.
- Significant structural differences were observed in HDL from CAD patients compared to AVS patients, including triglyceride and phospholipid content.
Conclusions:
- HDL from CAD and AVS patients differentially regulate gene expression in cardiac adipocytes.
- This regulation appears to involve HDL lipid internalization and is influenced by the lipoprotein's structural characteristics.
- Targeting HDL-mediated gene regulation in cardiac adipocytes presents a potential therapeutic strategy for CAD and AVS.
Abstract:
Previous reports have described a statistical association between high-density lipoproteins (HDL) subclasses and the expression of genes coding for pro-calcifying proteins in the epicardial adipose tissue of patients with coronary artery disease (CAD) and aortic valvular stenosis (AVS). These results suggest a causal relationship between HDL and the regulation of gene expression in epicardial adipose tissue. However, there is no experimental evidence that supports this causal relationship. Therefore, we explored the effect of HDL isolated from CAD or AVS patients on the expression of OPN, BMP2, and BMP4, genes coding for proteins related to calcification, osteopontin, and bone morphogenetic proteins -2 and -4, respectively, and LEP, UCP, and PER, coding for leptin, uncoupling protein-1, and perilipin-2, respectively, proteins that confer phenotypic characteristics to adipocytes. The experiments were performed using a novel model of cardiac adipocytes differentiated in vitro from stromal cells of rabbit cardiac adipose tissue. AVS or CAD patients' HDL differentially modulated the expression of BMP4 and LEP, whereas HDL from both kinds of patients upregulated the OPN gene expression. A high concentration of triglycerides associated to small HDL and a higher concentration of phospholipids of large HDL from CAD patients than those from AVS individuals were the most remarkable structural differences. Finally, we demonstrated that cholesterol from reconstituted HDL was internalized to the adipocytes. The regulation of genes related to the secretory activity of cardiac adipocytes mediated by HDL has clinical implications as a potential therapeutic target for the prevention and treatment of CAD and AVS. In summary, the HDL isolated from the CAD and AVS patients differentially regulated gene expression in adipocytes by a mechanism that seems to be dependent on HDL lipid internalization to the cells and structural characteristics of the lipoproteins.
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