Background: Cardiotrophin-1 (CT-1), a cytokine belonging to the interleukin-6 family, is increased in hypertension and in heart failure. We hypothesized that CT-1 excess promotes vascular fibrosis and dysfunction, whereas CT-1 deficiency influences lifespan by decreasing arterial stiffness.

Methods: CT-1 or vehicle were administrated to Wistar rats for 6 weeks, and 29 month-old WT and CT-1-null mice were used. Vascular function was analysed in vivo using echotracking device and ex vivo employing a scanning acoustic microscopy. Vascular histomorphology, senescence, metabolic, inflammatory and oxidative stress parameters were measured by immunohistochemistry, RT-PCR, Western Blot and ELISA.

Results: CT-1 treatment did not modify blood pressure levels. In CT-1-treated rats, the circumferential wall stress-incremental elastic modulus curve was shifted leftward and the acoustic speed of sound in the aorta was augmented, indicating increased arterial stiffness. Vascular media thickness, collagen and fibronectin content were increased by CT-1 treatment. The wall stress-incremental elastic modulus curve of old CT-1-null mice was shifted rightward as compared to WT, indicating decreased arterial stiffness. Media thickness and wall fibrosis were lower in CT-1-null mice. CT-1-null mice showed decreased levels of inflammatory, apoptotic and senescence pathways, whereas telomere-linked proteins, DNA repair proteins and antioxidant enzyme activities were increased. CT-1-null mice displayed a 5-month increased median longevity compared with WT.

Conclusion: CT-1 is a new potent vascular fibrotic agent able to induce arterial stiffness independently from blood pressure. CT-1 absence is associated with decreased arterial fibrosis, stiffness and senescence and increased longevity in mice likely through downregulating apoptotic, senescence and inflammatory pathways. CT-1 may be a major regulator of arterial stiffness with a major impact on the aging process.