Atorvastatin and Fenofibrate Exert Opposite Effects on the Vascularization and Characteristics of Visceral Adipose Tissue in New Zealand White Rabbits

Abstract

Statins may precipitate the onset of type 2 diabetes (T2D) in high-risk patients. In contrast, only the subset of individuals with insulin resistance and/or diabetes receives cardiovascular benefits with fibrates. In this context, previous observations from our laboratory suggested that atorvastatin induced an increase in visceral adipose tissue (VAT), whereas fenofibrate had the opposite effects in rabbits. Therefore, we determined the mass, morphology, and vascularization of VAT in New Zealand white rabbits (n = 6/group) that received 0.33 or 2.6 mg/kg/d of atorvastatin or fenofibrate, respectively, during 2 months. As expected, the cholesterol from the atorvastatin group was lower after treatment, while triglycerides decreased in the fenofibrate group. The mass of VAT from the fenofibrate group was 46% lower compared to the controls, meanwhile atorvastatin was associated with a larger diameter of adipocytes (+65%) than that of the control and fenofibrate groups. Fibroblast growth factor 2 ( FGF2) gene expression was lower in the fenofibrate group than in the control group (−54%). By contrast, vascular endothelial growth factor A (VEGF-A) gene expression in fenofibrate-treated rabbits was 110% higher than in the control group. In agreement with the gene expression, the marker of angiogenesis platelet endothelial cell adhesion molecule 1 was slightly but significantly higher (+10%) in rabbits treated with fenofibrate than in controls, as determined by immunohistochemistry. These results suggest that fenofibrate is associated with a favorable remodeling of VAT, that is, reduced mass and increased vascularization in normolipemic rabbits; in contrast, atorvastatin induced a nonfavorable remodeling of VAT. These results may be related to the cardiovascular benefits of fenofibrate and the increased risk of T2D in high-risk patients induced by atorvastatin.

<p>Bone Morphogenetic Protein-2 and Osteopontin Gene Expression in Epicardial Adipose Tissue from Patients with Coronary Artery Disease Is Associated with the Presence of Calcified Atherosclerotic Plaques</p>

“…mRNA from EAT samples was quantified as previously described with slight modifications. 16 Briefly, total RNA was isolated by using the Ribozol™ Plus RNA Purification Kit (Ameresco, OH, USA) following the manufacturer's instructions. The contaminant DNA was removed from total RNA with RNAse-free DNAse (Invitrogen, Life Technologies, Carlsbad, CA, USA).…”

High-Dose Fenofibrate Stimulates Multiple Cellular Stress Pathways in the Kidney of Old Rats

“…In our model, FF age-independently elevated the renal levels of VEGFA protein, despite decreased Vegfa mRNA after low-dose FF, suggestive of post-transcriptional mechanisms of regulation. Using bioinformatics tools, FF has been previously predicted to increase VEGFA expression in diabetic nephropathy [ 39 ], while the drug has been shown to increase VEGFA levels in the visceral adipose tissue of FF-treated normolipemic rabbits [ 40 ]. Moreover, in both young and old rats in our model, low-dose FF inhibited the expression of Serpine1 , activated by HIF-1 under hypoxic conditions [ 15 ].…”

Integrated Bioinformatics and Clinical Correlation Analysis of Key Genes, Pathways, and Potential Therapeutic Agents Related to Diabetic Nephropathy

“…To predict the potential effective therapy for DN associated with VEGFA, we applied the DGIDB database to determine therapeutic agents that might reverse the abnormally downregulated expression of VEGFA in DN. By checking drugs one-by-one in the network, we found that enalapril [ 24 ], sildenafil [ 25 ], and fenofibrate [ 26 ] positively regulate VEGFA. Enalapril is a commonly used drug to lower blood pressure and protect kidney function, fenofibrate is known as an important lipid-lowering drug, and sildenafil is an effective vasodilator.…”