title: Absence of cardiotrophin 1 is associated with decreased age-dependent arterial stiffness and increased longevity in mice.
abstract: Cardiotrophin 1 (CT-1), an interleukin 6 family member, promotes fibrosis and arterial stiffness. We hypothesized that the absence of CT-1 influences arterial fibrosis and stiffness, senescence, and life span. In senescent 29-month-old mice, vascular function was analyzed by echotracking device. Arterial histomorphology, senescence, metabolic, inflammatory, and oxidative stress parameters were measured by immunohistochemistry, reverse transcription polymerase chain reaction, Western blot, and ELISA. Survival rate of wild-type and CT-1-null mice was studied. Vascular smooth muscle cells were treated with CT-1 (10(-9) mol/L) for 15 days to analyze senescence. The wall stress-incremental elastic modulus curve of old CT-1-null mice was shifted rightward as compared with wild-type mice, 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 wild-type mice. In vascular smooth muscle cells, chronic CT-1 stimulation upregulated apoptotic and senescence markers and downregulated telomere-linked proteins. The absence of CT-1 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U961, Faculty of Medicine, Vandoeuvre-lès-Nancy, France. nlopand@alumni.unav.es
authors.forename: Natalia
authors.initials: N
authors.lastname: López-Andrés
authors.forename: Laurent
authors.initials: L
authors.lastname: Calvier
authors.forename: Carlos
authors.initials: C
authors.lastname: Labat
authors.forename: Renaud
authors.initials: R
authors.lastname: Fay
authors.forename: Javier
authors.initials: J
authors.lastname: Díez
authors.forename: Athanase
authors.initials: A
authors.lastname: Benetos
authors.forename: Faiez
authors.initials: F
authors.lastname: Zannad
authors.forename: Patrick
authors.initials: P
authors.lastname: Lacolley
authors.forename: Patrick
authors.initials: P
authors.lastname: Rossignol
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002339:Carotid Arteries / Q000378:metabolism*; D059168:Carotid Intima-Media Thickness; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D005355:Fibrosis; D008136:Longevity / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D051381:Rats; D059289:Vascular Stiffness / Q000235:genetics / Q000502:physiology*
chemical_list: D016207:Cytokines; C092073:cardiotrophin 1