Abstract
Caveolin-1 (CAV-1) participates in regulating vesicular transport, signal transduction, tumor progression, and cholesterol homeostasis. In the present study, we tested the hypothesis that CAV-1 improves dyslipidemia, inhibits cyclophilin A (CypA)- mediated ROS production, prevents mitochondrial compensatory action and attenuates oxidative stress responses in cholesterol-induced hypercholesterolemia. To determine the role of CAV-1 in mediating oxidative and antioxidative as well as cholesterol homeostasis, hypercholesterolemic rabbits were intravenously administered antenapedia-CAV-1 (AP-CAV-1) peptide for 2 wk. AP-CAV-1 enhanced CAV-1 expression by ˃15%, inhibited CypA expression by ˃50% (P < 0.05) and significantly improved dyslipidemia, thus reducing neutral lipid peroxidation. Moreover, CAV-1 attenuated hypercholesterolemia-induced changes in mitochondrial morphology and biogenesis and preserved mitochondrial respiratory function. In addition, CAV-1 protected against hypercholesterol-induced oxidative stress responses by reducing the degree of oxidative damage and enhancing the expression of antioxidant enzymes. CAV-1 treatment significantly suppressed apoptotic cell death, as evidenced by the reduction in the number of terminal deoxynucleotidyl transferase dUTP nick end-labeling-positive cells. We concluded that CAV-1 plays a critical role in inhibiting CypA-mediated ROS production, improving dyslipidemia, maintaining mitochondrial function, and suppressing oxidative stress responses that are vital for cell survival in hypercholesterol-affected renal organs.
Highlights
Caveolin-1 (CAV-1) is a cholesterol- and sphingomyelin-binding protein responsible for caveolae formation
Based on renal section analysis, the staining intensity of CAV-1 was higher in the AP-CAV1-treated high-cholesterol diet with AP-CAV-1 (HCAV-1) group than in the highcholesterol diet controls (HCs) group and normal diet controls (NCs) rabbits
AP-CAV-1 markedly reduced the number of cyclophilin A (CypA)-positive cells, which induce inflammation, in the AP-CAV-1-treated HCAV-1 group compared with the HC group (4.7 ± 3.1 vs. 10.1 ± 2.7 positive cells/400× field, P 0.05, Fig 1A and 1B and Dataset in S1 File)
Summary
Caveolin-1 (CAV-1) is a cholesterol- and sphingomyelin-binding protein responsible for caveolae formation. It is highly expressed in vascular endothelial cells, adipocytes, smooth. CAV-1 Ameliorates Hypercholesterolemia-Induced Nephropathy muscle cells, and fibroblasts [1]. It plays an essential role in regulating vesicular transport, signal transduction, tumor progression, and cholesterol homeostasis [2,3]. Several studies have revealed that CAV-1 protein overexpression markedly reduced total cholesterol and free cholesterol (FC) content as well as their accumulation in lipid-loading cells [6,7,8]. Frank et al demonstrated that CAV-1 is proatherogenic in endothelial cells, whereas it is antiatherogenic in smooth muscle cells and macrophages [12,13]. Demonstrating the cell-specific role of CAV-1 during the development of related-disease may be crucial
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