1Justus-Liebig-Universität Giessen Experimentelle Kardiologie Gießen, Deutschland; 2Physiologisches Institut Gießen, Deutschland; 3Universitätsklinikum Gießen und Marburg GmbH Klinik für Herz-, Kinderherz- und Gefäßchirurgie Gießen, Deutschland; 4Justus-Liebig-Universität Giessen Physiologisches Institut Gießen, Deutschland
Background: Secreted endocrine hormones and cytokines play a crucial role in the communication between different organs and cells. Members of the complement 1q (C1q)/tumor necrosis factor (TNF)-related protein (CTRP) family are secreted proteins composed of a C-terminal globular C1q (gC1q) domain and an N-terminal variable domain. The adipocytokine adiponectin is the best studied representative of this family and an important regulator of glucose and lipid metabolism. Besides adiponectin, 15 other structurally related ligands exist, from CTRP1 to CTRP15. Here, we investigated the vascular effects of CTRP13.
Results: CTRP13 is not only expressed in adipose tissue but also in vessels/endothelial cells (ECs) of mice, rats and humans. Obese mice (ob/ob) and rats (ZDF) showed a significantly higher CTRP13 expression in the aorta. A similar obesity-associated effect was also observed in mammary arteries of patients undergoing cardiac surgery. Plasma glucose and insulin were increased in obese mice and rats and moderately higher fasting glucose was also observed in obese patients. Human Umbilical Vein Endothelial Cells (HUVECs), cultured in the presence of serum from obese mice, mimicked this demonstrated obesity-associated effect on endothelial cells (EC) CTRP13 protein expression. Similarly, high glucose condition and/or TNF-alpha but not insulin resulted in a strong increase in CTRP13 in these cells. Recombinant CTRP13 induced a reduction in EC proliferation and migration via AMPK. In addition, CTRP13 reduced cell cycle progression, increased p53 phosphorylation and p21 protein expression but reduced Rb phosphorylation, effects largely depending on alpha-2 AMPK as suggested by adenoviral overexpression of dominant-negative (DN) or wild-type (WT) alpha 1/alpha 2 AMPK.
Conclusion: The present study demonstrates that CTRP13 expression is induced in ECs in vitro and in vessels in vivo in different species under diabetic conditions. In particular TNF-alpha, which is known to play a crucial role to induce insulin resistance and pathogenesis, was a strong modulator of endothelial CTRP13 expression. CTRP13 possess significant vaso-modulatory properties which may have an impact on vascular disease progression in patients, but appear to be unfavorable unlike the vascular effects of adiponectin.