Protective effect of apelin-13 against hypercholesterolemia-induced fibrosis of the corpus cavernosum
Sturny, M1; Anguenot, L1; Martins Lima, A1; Bragina, M1; Costa-Fraga, F1; da Silva, R2; Fraga-Silva, R1; Stergiopulos, N1
1: EPFL, Switzerland; 2: UFMG, Brazil
Objectives: Apelin, an endogenous circulating peptide, has been documented as an important effector on cardiovascular homeostasis, controlling vascular function and structure. Initial studies have shown that apelin, acting through APJ receptor, may also modulate penile erection. However, the role of apelin/APJ receptor on penile collagen remodelling has never been investigated. Here we sought to evaluate the effect of apelin treatment on penile structure of hypercholesterolemic mice and its mechanism of action.
Material and Methods: Apolipoprotein E gene-deleted (ApoE-/-) mice were fed with Western diet for 11 weeks and received apelin-13 (2mg/kg) or vehicle during the last 3 weeks. Penile samples were obtained for histological and biochemical analyses. Furthermore, the effect of apelin-13 on fibroblast to myofibroblasts differentiation and collagen production was evaluated in cultured mouse fibroblast.
Results: Apelin and APJ receptor were expressed (gene and protein) within the corpus cavernosum of ApoE-/- mice, indicating a local modulation of apelin system. Remarkably, three weeks of treatment with apelin-13 strongly reduced intracavernosal collagen content in hypercholesterolemic ApoE-/- mice. This effect was accompanied by total matrix metalloproteinase (MMP) activity and expression increase within mice penis, while tissue inhibitor of metalloproteinase (TIMP) were unaltered. These beneficial actions were associated with a serum lipid profile improvement, but not with alteration on atherosclerotic plaque deposition, nor intracavernosal NO bioavailability/ROS content. Interestingly, apelin-13 inhibited TGF-β-induced fibroblast to myofibroblast differentiation and collagen production in cell culture through activation of ERK1/2 kinase.
Conclusion: These results suggest a local modulation of apelin/APJ system within the corpus cavernosum. Remarkably, apelin-13 attenuated hypercholesterolemic-induced cavernosal fibrosis by: 1) enhancing MMPs expression and activity; 2) inhibiting fibroblast differentiation into myofibroblast; and 3) diminishing collagen production. These results provide the first evidence of apelin/APJ system as modulator of erectile tissue structure/remodelling, and point out this system as a novel potential target to treat intracavernosal fibrosis-related disorders.
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